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METHODS OF IDENTIFYING HIV PATIENTS SENSITIVE TO THERAPY WITH GP120 V3 GLYCAN-DIRECTED ANTIBODIES

20200368347 ยท 2020-11-26

    Inventors

    Cpc classification

    International classification

    Abstract

    Provided are methods for identifying patient populations infected with HIV that can be targeted by antibodies that bind to HIV gp120 V3 glycan region.

    Claims

    1. A method of treating or preventing HIV in a human subject in need thereof, the method comprising: a) Identifying a human subject who is infected with an HIV or a population of HIV expressing a gp120 comprising the following amino acid residues: N332glycan, D325, and one or more amino acid residues selected from the group consisting of T63, L179, T320, and H330, wherein the amino acid positions are with reference to SEQ ID NO: 4; and b) Administering to the subject an effective amount of an antibody or antigen-binding fragment thereof that competes with or comprises VH and VL regions that bind to an epitope of gp120 within the third variable loop (V3) and/or high mannose patch comprising a N332 oligomannose glycan.

    2. The method of claim 1, comprising identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising the following amino acid residues: i. N332glycan, D325 and T63; ii. N332glycan, D325 and L179; iii. N332glycan, D325 and T320; iv. N332glycan, D325 and H330; v. N332glycan, D325, T63 and L179; vi. N332glycan, D325, T63 and T320; vii. N332glycan, D325, T63 and H330; viii. N332glycan, D325, L179 and T320; ix. N332glycan, D325, L179 and H330; x. N332glycan, D325, T320 and H330; xi. N332glycan, D325, T63, T320 and H330; xii. N332glycan, D325, T63, L179 and T320; xiii. N332glycan, D325, T63, L179 and H330; xiv. N332glycan, D325, L179, T320 and H330; or xv. N332glycan, D325, T63, L179, T320 and H330.

    3. The method of claim 1, comprising identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising the following amino acid residues: i. N332glycan, D325 and T63; ii. N332glycan, D325 and L179; iii. N332glycan, D325 and T320; or iv. N332glycan, D325 and H330.

    4. The method of claim 1, comprising identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising the following amino acid residues: i. N332glycan, D325, T63 and L179; ii. N332glycan, D325, T63 and T320; iii. N332glycan, D325, T63 and H330; iv. N332glycan, D325, L179 and T320; v. N332glycan, D325, L179 and H330; or vi. N332glycan, D325, T320 and H330.

    5. The method of claim 1, comprising identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising the following amino acid residues: i. N332glycan, D325, L179, T320 and H330; ii. N332glycan, D325, T63, T320 and H330; iii. N332glycan, D325, T63, L179 and T320; or iv. N332glycan, D325, T63, L179 and H330.

    6. The method of claim 1, comprising identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising the following amino acid residues: i. N332glycan, D325, T63 and H330; ii. N332glycan, D325, T320 and H330; iii. N332glycan, D325, L179, T320 and H330; or iv. N332glycan, D325, T63, L179, T320 and H330.

    7. The method of claim 1, wherein the subject is infected with an HIV or a population of HIV expressing a gp120 further comprising one or more of the following amino acid residues: i. glycan301; ii. K677; iii. not_W17; iv. not_R747; v. insertion_321.01; vi. E429; vii. Q442; viii. R335; ix. I165; x. S393; xi. I307; xii. 295 glycan; and/or xiii. N300.

    8. The method of claim 1, wherein at least 90%, e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%, of the HIV species in the population of HIV comprise the recited amino acid residues.

    9. The method of claim 1, wherein the administered antibody or antigen-binding fragment thereof competes with or comprises VH and VL regions from an antibody selected from the group consisting of GS-9722, GS-9721, PGT-121, PGT-121.66, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, GS-2872, 10-1074, 10-1074-J, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03.

    10. The method of claim 1, wherein the antibody or antigen-binding fragment thereof competes with or comprises VH and VL regions from an antibody selected from the group consisting of GS-9722, GS-9721, PGT-121, PGT-121.66, PGT-121.414, PGT-124, PGT-134, GS-2872, 10-1074, 10-1074-J, PGT-122 and PGT-123.

    11. The method of claim 1, wherein the antibody comprises an Fc region comprising the following amino acids at the indicated positions (EU index numbering): i. Tyrosine at position 252, threonine at position 254 and glutamic acid at position 256 (YTE); or ii. Leucine at position 428 and serine at position 434 (LS).

    12. The method of claim 1, wherein the antibody comprises an Fc region comprising the following amino acids at the indicated positions (EU index numbering): i. Aspartate at position 239 and glutamate at position 332 (DE); ii. Aspartate at position 239, glutamate at position 332 and leucine at position 330 (DEL); iii. Aspartate at position 239, glutamate at position 332, alanine at position 236 (DEA); or iv. Aspartate at position 239, glutamate at position 332, alanine at position 236 and leucine at position 330 (DEAL).

    13. The method of claim 1, comprising administering an antigen binding fragment.

    14. The method of claim 13, wherein the antigen binding fragment is selected from the group consisting of scFv, Fab, Fab2, Fab, F(ab)2, Fv, and a diabody.

    15. The method of claim 1, wherein the antibody is a multi-specific antibody.

    16. The method of claim 1, wherein the human subject is acutely infected with HIV.

    17. The method of claim 16, wherein the antibody is administered to a human subject having an HIV infection of Fiebig stage IV or earlier.

    18. The method of claim 16, wherein the antibody is administered to a human subject who has not seroconverted.

    19. The method of claim 1, wherein the human subject is recently infected with HIV.

    20. The method of claim 19, wherein the antibody is administered to a human subject having an HIV infection of Fiebig stage V or Fiebig stage VI.

    21. The method of claim 1, wherein the human subject is chronically infected with HIV.

    22. The method of claim 1, wherein the human subject is infected with HIV clade B viruses.

    23. The method of claim 22, comprising identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising the following amino acid residues: i. N332glycan, D325, T63 and H330; ii. N332glycan, D325, L179, T320 and H330; or iii. N332glycan, D325, T63, L179, T320 and H330.

    24. The method of claim 1, wherein the human subject is infected with HIV clade A viruses.

    25. The method of claim 1, wherein the human subject is infected with HIV clade C viruses.

    26. The method of claim 1, further comprising administering to the subject one or more additional therapeutic agents for treating an HIV infection.

    27. The method of claim 1, wherein the subject is not receiving antiretroviral therapy (ART) or ART is discontinued prior to administration of the antibody.

    28. The method of claim 1, wherein ART is discontinued after one or more administrations of the antibody or antigen-binding fragment thereof.

    29. The method of claim 1, further comprising administering one or more antiretroviral therapy (ART) agents to the subject.

    30. The method of claim 1, further comprising administering to the subject a second antibody or antigen binding fragment thereof that binds to an epitope or region of gp120 selected from the group consisting of: i. second variable loop (V2) and/or Env trimer apex; ii. CD4 binding site (CD4bs); iii. gp120/gp41 interface; or iv. silent face of gp120.

    31. The method of claim 30, wherein the second antibody or antigen-binding fragment thereof binds to an epitope or region of gp120 in the second variable loop (V2) and/or Env trimer apex and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PG9, PG16, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CH01, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01.

    32. The method of claim 30, wherein the second antibody or antigen-binding fragment thereof binds to an epitope or region of gp120 in the CD4 binding site (CD4bs) and competes with or comprises VH and VL regions from an antibody selected from the group consisting of b12, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 VRC08, VRC0801, NIH45-46, GS-9723, GS-5423, 3BNC117, 3BNC60, VRC-PG04, PGV04; CH103, 44-VRC13.01, 1NC9, 12A12, N6, N6LS (VRC-HIVMAB091-00-AB), N49-P7, NC-Cow1, IOMA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9 and N60P25.

    33. The method of claim 30, wherein the second antibody or antigen-binding fragment thereof binds to an epitope or region of gp120 in the gp120/gp41 interface and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PGT-151, CAP248-2B, 35O22, 8ANC195, ACS202, VRC34 and VRC34.01.

    34. The method of claim 30, wherein the second antibody or antigen-binding fragment thereof binds to an epitope or region of the gp120 silent face and competes with or comprises VH and VL regions from antibody VRC-PG05.

    35. The method of claim 30, wherein the second antibody or antigen-binding fragment thereof binds to an epitope or region of gp41 in the membrane proximal region (MPER) and competes with or comprises VH and VL regions from an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01.

    36. The method of claim 30, wherein the second antibody or antigen-binding fragment thereof binds to an epitope or region of the gp41 fusion peptide and competes with or comprises VH and VL regions from an antibody selected from the group consisting of VRC34 and ACS202.

    37. The method of claim 1, further comprising administering to the subject a TLR agonist.

    38. The method of claim 37, wherein the TLR agonist is a TLR2 agonist, a TLR3 agonist, a TLR7 agonist, a TLR8 agonist or a TLR9 agonist.

    39. The method of claim 38, wherein the TLR7 agonist is selected from the group consisting of vesatolimod, imiquimod, and resiquimod.

    40. The method of claim 1, comprising multiple administrations of the antibody or antigen-binding fragment thereof, optionally with a TLR agonist, at predetermined intervals.

    41. The method of claim 1, wherein, after one or more administrations of the antibody or antigen-binding fragment thereof, the subject does not exhibit symptoms of HIV or AIDS in the absence of anti-retroviral treatment (ART) for at least 6 months, at least 1 year, at least 2 years, at least 3 years, or more.

    42. The method of claim 1, wherein, after one or more administrations of the antibody, the subject has a viral load copies/ml blood of less than 500, e.g., less than 400, less than 300, less than 200, less than 100, less than 50, in the absence of anti-retroviral treatment (ART) for at least 6 months, at least 1 year, at least 2 years, at least 3 years, or more.

    43. A method of identifying a human subject infected with an HIV or a population of HIV sensitive to an antibody or antigen-binding fragment thereof that competes with or comprises VH and VL regions that bind to an epitope of gp120 within the third variable loop (V3) and/or high mannose patch comprising a N332 oligomannose glycan, the method comprising identifying in a biological sample from the human subject an HIV expressing a gp120 comprising the following amino acid residues: N332glycan, D325, and one or more amino acid residues selected from the group consisting of T63, L179, T320, and H330, wherein the amino acid positions are with reference to SEQ ID NO: 4.

    44-66. (canceled)

    67. The method of claim 1, wherein the gp120 amino acids are identified in one or more biological samples from the subject, wherein the one or more biological sample are obtained from blood, peripheral blood mononuclear cells (PBMCs), serum, plasma, semen or lymph nodes.

    68. The method of claim 1, comprising identifying a population of HIV RNA in a serum or plasma sample.

    69. The method of claim 1, further comprising the step of obtaining one or more biological samples from the subject.

    70. The method of claim 69, wherein two or more biological samples are obtained from the subject.

    71. The method of claim 70, wherein the two or more biological samples are obtained from the same tissue or fluid at two or more different time points.

    72. The method of claim 70, wherein the two or more biological samples are obtained from different tissues or fluids, or from different anatomical locations.

    Description

    BRIEF DESCRIPTION OF THE DRAWINGS

    [0074] FIG. 1 illustrates the number of screened subjects from the Zurich Primary HIV Infection Cohort Study with a genotype predicting sensitivity to GS-9722 (elipovimab). Pre-ART plasma samples from 92 individuals were analyzed in the GenoSure HIV Envelope RNA Assay. None, indicates all screened individuals without selection for specific amino acids in the HIV envelope gene. Amino acid positions indicated for each category.

    [0075] FIG. 2 illustrates the number of screened clade B subjects from the Zurich Primary HIV Infection Cohort Study with a genotype predicting sensitivity to GS-9722. Pre-ART plasma samples from 59 clade B infected individuals were analyzed in the GenoSure HIV Envelope RNA Assay. None, indicates all screened individuals without selection for specific amino acids in the HIV envelope gene. Amino acid positions indicated for each category.

    [0076] FIG. 3 illustrates the sensitivity to GS-9722 for swarm viruses derived from pre-ART plasma samples from the Zurich Primary HIV Infection Cohort Study. Virus from 29 samples with positive predictive values of 80.7% or higher were analyzed in the PHENOSENSE HIV Entry Assay (Monogram Biosciences). Amino acid positions indicated for each category.

    [0077] FIG. 4 illustrates the sensitivity to GS-9722 for viruses subcloned from swarm viruses derived from pre-ART plasma samples from the Zurich Primary HIV Infection Cohort Study. Twenty individual viruses from four pre-ART plasma samples, where swarm viruses were predicted sensitive by genotyping and tested sensitive by phenotyping, were analyzed in the PHENOSENSE HIV Entry Assay (Monogram Biosciences). Solid line indicates IC50 for swarm virus.

    DETAILED DESCRIPTION

    [0078] 1. Introduction

    [0079] The present methods are based, in part, on the unexpected discovery of HIV-infected patient populations who are responsive to the administration of an anti-HIV gp120 V3-glycan directed antibody or antigen-binding fragment thereof, in the absence of co-administration of additional anti-HIV antibodies directed against other HIV antigens (e.g., gp41) or non-overlapping epitopes of the same HIV antigen (e.g., directed against gp120 in the region of the CD4 binding site or V2 apex region). Such patients are infected with a species of HIV having a gp120 protein that is bound by a V3-glycan directed antibody or antigen-binding fragment thereof.

    [0080] Generally, the methods entail identifying a human subject who is infected with an HIV or a population of HIV expressing a gp120 comprising: a glycosylated asparagine at the position corresponding to amino acid residue position 332 (N332glycan), an aspartate at the position corresponding to amino acid residue position 325 (D325), and one or more amino acid of: a threonine at the position corresponding to amino acid residue position 63 (T63), a leucine at the position corresponding to amino acid residue position 179 (L179), a threonine at the position corresponding to amino acid residue position 320 (T320), and a histidine at the position corresponding to amino acid residue position 330 (H330), wherein the amino acid positions are with reference to SEQ ID NO: 4 (i.e., residues 1-511 of NCBI Ref Seq No. NP_057856.1). In various embodiments, the glycan is an oligomannose.

    [0081] 2. Identification of Subjects Responsive to Treatment with an Anti-HIV gp120 V3-Glycan Directed Antibody or Antigen-Binding Fragment Thereof.

    [0082] In some embodiments, the patient is identified by receiving a report of the HIV species infecting the patient that identifies the HIV gp120 amino acids residues present at the designated amino acid positions of interest, e.g., at positions 332 and 325, and one or more amino acid positions from the group consisting of: 63, 179, 320 and 330, wherein the amino acid positions are with reference to SEQ ID NO: 4. In some embodiments, the patient is identified by conducting one or more assays (e.g., polynucleotide or polypeptide sequencing) to determine the amino acid sequence(s) of the gp120 or the amino acid residues present at the designated amino acid positions of interest of the gp120 protein(s) of the HIV species infecting the patient. Identification of the full length or partial sequences of the gp120 proteins obtained from the subject can be determined at the polynucleotide or polypeptide level. In some embodiments, the amino acids present at the gp120 residue positions of interest are determined at the polypeptide level.

    [0083] In various embodiments, the methods entail identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising N332glycan, D325 and T63, wherein the amino acid positions are with reference to SEQ ID NO: 4.

    [0084] In various embodiments, the methods entail identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising N332glycan, D325 and L179, wherein the amino acid positions are with reference to SEQ ID NO: 4.

    [0085] In various embodiments, the methods entail identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising N332glycan, D325 and T320, wherein the amino acid positions are with reference to SEQ ID NO: 4.

    [0086] In various embodiments, the methods entail identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising N332glycan, D325 and H330, wherein the amino acid positions are with reference to SEQ ID NO: 4.

    [0087] In various embodiments, the methods entail identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising N332glycan, D325, T63 and L179, wherein the amino acid positions are with reference to SEQ ID NO: 4.

    [0088] In various embodiments, the methods entail identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising N332glycan, D325, T63 and T320, wherein the amino acid positions are with reference to SEQ ID NO: 4.

    [0089] In some embodiments, the subject is infected with HIV clade B viruses. In various embodiments, the methods entail identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising N332glycan, D325, T63 and H330, wherein the amino acid positions are with reference to SEQ ID NO: 4. In various embodiments, the methods entail identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising N332glycan, D325, T63, L179, T320 and H330, wherein the amino acid positions are with reference to SEQ ID NO: 4.

    [0090] In various embodiments, the methods entail identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising N332glycan, D325, T320 and H330, wherein the amino acid positions are with reference to SEQ ID NO: 4.

    [0091] In various embodiments, the methods entail identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising N332glycan, D325, L179, T320 and H330, wherein the amino acid positions are with reference to SEQ ID NO: 4. In some embodiments, the subject is infected with HIV clade A and/or HIV clade C viruses. In some embodiments, the subject is infected with HIV clade A, clade B and/or HIV clade C viruses.

    [0092] In various embodiments, the methods entail identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising N332glycan, D325, T63, L179 and T320, wherein the amino acid positions are with reference to SEQ ID NO: 4.

    [0093] In various embodiments, the methods entail identifying a subject infected with an HIV or a population of HIV expressing a gp120 comprising N332glycan, D325, T63, L179 and H330, wherein the amino acid positions are with reference to SEQ ID NO: 4.

    [0094] In some embodiments, the subject is infected with an HIV or a population of HIV expressing a gp120 further comprising one or more of the following amino acid residues: a glycan at amino acid residue 301 (glycan301); a lysine at amino acid residue 677 (K677); an amino acid residue other than tryptophan (Trp, W) (e.g., alanine (Ala, A); cysteine (Cys, C); aspartate or aspartic acid (Asp, D); glutamate or glutamic acid (Glu, E); phenylalanine (Phe, F); glycine (Gly, G); histidine (His, H); isoleucine (Ile, I); lysine (Lys, K); leucine (Leu, L); methionine (Met, M); asparagine (Asn, N); proline (Pro, P); glutamine (Gln, Q); arginine (Arg, R); serine (Ser, S); Threonine (Thr, T); valine (Val, V) or tyrosine (Tyr, Y)) at position 17 (not_W17); an amino acid residue other than arginine (e.g., A, C, D, E, F, G, H, I, K, L, M, N, P, Q, S, T, V, W or Y) at position 747 (not_R747); an insertion_321.01 (e.g., an insertion of any amino acid (e.g., A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y) between position G321 and K322); a glutamic acid at position 429 (E429); a glutamine at position 442 (Q442); an arginine at position 335 (R335); an isoleucine at position 165 (I165); a serine at position 393 (S393); an isoleucine at position 307 (I307); a glycan at position 295 (295 glycan); and/or an asparagine at position 300 (N300), wherein the amino acid positions are with reference to SEQ ID NO: 4.

    gp120

    [0095] Envelope glycoprotein gp120 (or gp120) is a 120 kDa glycoprotein that is part of the outer layer of HIV. It presents itself as viral membrane spikes consisting of three molecules of gp120 linked together and anchored to the membrane by gp41 protein. Gp120 is essential for viral infection as it facilitates HIV entry into the host cell through its interaction with cell surface receptors. These receptors include DC-SIGN, Heparan Sulfate Proteoglycan, and the CD4 receptor. Binding to CD4 on helper T-cells induces the start of a cascade of conformational changes in gp120 and gp41 that lead to the fusion of the virus with the host cell membrane.

    [0096] Gp120 is encoded by the HIV env gene. The env gene encodes a gene product of around 850 amino acids. The primary env product is the protein gp160, which gets cleaved to gp120 (about 480 amino acids) and gp41 (about 345 amino acids) in the endoplasmic reticulum by the cellular protease furin.

    [0097] The V3 glycan site on gp120 is formed partly by a section of the CCR5 coreceptor site and partly by the surrounding camouflaging glycans (so-called high mannose patch) (Sok, et al., Immunity (2016) 45, 31-45). Broadly neutralizing antibodies (bnAbs) to the V3 glycan site are the most common of all Abs found in HIV infection (Walker, et al., PLoS Pathog. (2010) 6:e1001028 (2010); Landais, et al., PLoS Pathog. (2016) 12:e1005369; Georgiev, et al. Science (2013) 340:751-756). A consensus sequence of the V3 region of gp120 (Milich et al., J Virol., 67(9):5623-5634 (1993) is provided below:

    TABLE-US-00001 (SEQIDNO:1) CTRPNNNTRKSIHIGPGRAFYTTGEIIGDIRQAHC.

    [0098] The amino acid sequence of an exemplary gp160 polypeptide of HIV clone WITO is provided below (the V3 hypervariable loop is boldened and the N332 potential N-linked glycosylation site is boldened and underlined):

    TABLE-US-00002 (SEQIDNO:2) MKVMGTKKNYQHLWRWGIMLLGMLMMSSAAEQLWVTVYYGVPVWREANTT LFCASDAKAYDTEVHNVWATHACVPTDPNPQEVVMGNVTEDFNMWKNNMV EQMHEDIISLWDQSLKPCVKLTPLCVTLHCTNVTISSTNGSTANVIMREE MKNCSFNTTTVIRDKIQKEYALFYKLDIVPIEGKNTNTSYRLINCNTSVI TQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGKGPCRNVSTVQCTHGI KPVVSTQLLLNGSLAEEDIIIRSENFTNNGKNIIVQLKEPVKINCTRPGN NTRRSINIGPGRAFYATGAIIGDIRKAHCNISTEQWNNTLTQIVDKLREQ FGNKTIIFNQSSGGDPEVVMHTFNCGGEFFYCNSTQLFNSTWFNNGTSTW NSTADNITLPCRIKQVINMWQEVGKAMYAPPIRGQIDCSSNITGLILTRD GGSNSSQNETFRPGGGNMKDNWRSELYKYKVVKIEPLGIAPTRAKRRVVQ REKRAVTLGAVFLGFLGAAGSTMGAASLTLIVQARLLLSGIVQQQSNLLR AIEAQQHMLQLTVWGIKQLQARVLAIERYLKDQQLLGIWGCSGKLICTTT VPWNTSWSNKSYDYIWNNMTWMQWEREIDNYTGFIYTLIEESQNQQEKNE LELLELDKWASLWNWFNITNWLWYIKLFIMIIGGLVGLRIVCAVLSIVNR VRQGYSPLSFQTRLPNPRGPDRPEETEGEGGERDRDRSARLVNGFLAIIW DDLRSLCLFSYHRLRDLLLIVARVVEILGRRGWEILKYWWNLLKYWSQEL KNSAVSLLNVTAIAVAEGTDRVIEIVQRAVRAILHIPTRIRQGFERALL

    [0099] The amino acid sequence of an exemplary gp160 polypeptide of HIV clone identified in NCBI Ref Seq No. NP_057856.1 is provided below (the V3 hypervariable loop is boldened and the N332 potential N-linked glycosylation site is boldened and underlined):

    TABLE-US-00003 (SEQIDNO:3) MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTVYYGVPVWKEATT TLFCASDAKAYDTEVHNVWATHACVPTDPNPQEVVLVNVTENFNMWKNDM VEQMHEDIISLWDQSLKPCVKLTPLCVSLKCTDLKNDTNTNSSSGRMIME KGEIKNCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYKLTSCNTSV ITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCTHG IRPVVSTQLLLNGSLAEEEVVIRSVNFTDNAKTIIVQLNTSVEINCTRPN NNTRKRIRIQRGPGRAFVTIGKIGNMRQAHCNISRAKWNNTLKQIASKLR EQFGNNKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQLFNSTWFNSTW STEGSNNTEGSDTITLPCRIKQIINMWQKVGKAMYAPPISGQIRCSSNIT GLLLTRDGGNSNNESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTK AKRRVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQLLSGIVQ QQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQQLLGIWGCSG KLICTTAVPWNASWSNKSLEQIWNHTTWMEWDREINNYTSLIHSLIEESQ NQQEKNEQELLELDKWASLWNWFNITNWLWYIKLFIMIVGGLVGLRIVFA VLSIVNRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRLVN GSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKYWWNLL QYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQGACRAIRHIPRRIRQG LERILL

    [0100] The amino acid sequence of an exemplary gp120 polypeptide of HXB2 subtype B HIV-1 isolate (GenBank Accession No. K0345; corresponding to residues 1-511 of NCBI Ref Seq No. NP_057856.1) is provided below (the V3 hypervariable loop is boldened and the N332 potential N-linked glycosylation site is boldened and underlined; signal peptide is underlined):

    TABLE-US-00004 (SEQIDNO:4) MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTVYYGVPVWKEATT TLFCASDAKAYDTEVHNVWATHACVPTDPNPQEVVLVNVTENFNMWKNDM VEQMHEDIISLWDQSLKPCVKLTPLCVSLKCTDLKNDTNTNSSSGRMIME KGEIKNCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYKLTSCNTSV ITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCTHG IRPVVSTQLLLNGSLAEEEVVIRSVNFTDNAKTIIVQLNTSVEINCTRPN NNTRKRIRIQRGPGRAFVTIGKIGNMRQARCNISRAKWNNTLKQIASKLR EQFGNNKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQLFNSTWFNSTW STEGSNNTEGSDTITLPCRIKQIINMWQKVGKAMYAPPISGQIRCSSNIT GLLLTRDGGNSNNESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTK AKRRVVQREKR

    [0101] The amino acid sequence of an exemplary gp120 polypeptide is provided below:

    TABLE-US-00005 (SEQIDNO:5) AEQLWVTVYYGVPVWREANTTLFCASDAKAYDTEVHNVWATHACVPTDPN PQEVVMGNVTEDFNMWKNNMVEQMHEDIISLWDQSLKPCVKLTPLCVTLH CTNVTISSTNGSTANVTMREEMKNCSFNTTTVIRDKIQKEYALFYKLDIV PIEGKNTNTSYRLINCNTSVITQACPKVSFEPIPIHYCAPAGFAILKCNN KTFNGKGPCRNVSTVQCTHGIKPVVSTQLLLNGSLAEEDIIIRSENFTNN GKNIIVQLKEPVKINCTRPGNNTRRSINIGPGRAFYATGAIIGDIRKAHC NISTEQWNNTLTQIVDKLREQFGNKTIIFNQSSGGDPEVVMHTFNCGGEF FYCNSTQLFNSTWFNNGTSTWNSTADNITLPCRIKQVINMWQEVGKAMYA PPIRGQIDCSSNITGLILTRDGGSNSSQNETFRPGGGNMKDNWRSELYKY KVVKIEPLGIAPTRAKRRVVQREKR.

    [0102] The amino acid sequence of another exemplary gp120 polypeptide (see, bioafrica.net/proteomics/ENV-GP120prot.html) is provided below:

    TABLE-US-00006 (SEQIDNO:6) TEKLWVTVYYGVPVWKEATTTLFCASDAKAYDTEVHNVWA THACVPTDPNPQEVVLVNVTENFNMWKNDMVEQMHEDIIS LWDQSLKPCVKLTPLCVSLKCTDLKNDTNTNSSSGRMIME KGEIKNCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTS YKLTSCNTSVITQACPKVSFEPIPIHYCAPAGFAILKCNN KTFNGTGPCTNVSTVQCTHGIRPVVSTQLLLNGSLAEEEV VIRSVNFTDNAKTIIVQLNTSVEINCTRPNNNTRKRIRIQ RGPGRAPVTIGKIGNMRQAHCNISRAKWNNTLKQIASKLR EQFGNNKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQL FNSTWFNSTWSTEGSNNTEGSDTITLPCRIKQIINMWQKV GKAMYAPPISGQIRCSSNITGLLLTRDGGNSNNESEIFRP GGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKRRVVQREKR

    [0103] Genomic diversity among independent human immunodeficiency virus type 1 (HIV-1) isolates, to a lesser degree among sequential isolates from the same patients, and even within a single patient isolate is a well-known feature of HIV-1. Although this sequence heterogeneity is distributed throughout the genome, most of the heterogeneity is located in the env gene. Comparison of predicted amino acid sequences from several different isolates has shown that sequence heterogeneity is clustered in five variable regions (designated V1 through V5) of the surface glycoprotein, gp120. The V3 region, although only 35 amino acids long, exhibits considerable sequence variability. Interestingly, despite this variability, the V3 region includes determinants that mediate interactions with CD4.sup.+ cells. The increase in gp120 variability results in higher levels of viral replication, suggesting an increase in viral fitness in individuals infected by diverse HIV-1 variants. Variability in potential N-linked glycosylation sites (PNGSs) also result in increased viral fitness. PNGSs allow for the binding of long-chain carbohydrates to the high variable regions of gp120. Thus, the number of PNGSs in env might affect the fitness of the virus by providing more or less sensitivity to neutralizing antibodies.

    Biological Sample

    [0104] The HIV gp120 amino acid residues of interest are determined from HIV present or suspected to be present in a biological sample from the subject. The biological sample can be from a solid tissue or biological fluid of the subject known or suspected to contain HIV. In various embodiments, the biological sample comprises or is from blood, peripheral blood mononuclear cells (PBMCs), serum, plasma, semen or lymph nodes. In some embodiments, the biological sample comprises or is from bile, blood, blood plasma, serum, breast milk, feces, pus, saliva, sebum, semen, sweat, tears, urine, or vomit. In patients whose virus levels are suppressed, e.g., by antiretroviral (ART) therapy, the biological sample comprises solid tissue or biological fluid of the subject known or suspected to contain an HIV reservoir, e.g., solid tissues and/or biological fluids comprising latently HIV-infected CD4+ T cells (including memory and non-memory effector CD4+ T cells), hematopoietic progenitors of CD4+ T cells, T cells (including memory and non-memory effector T cells), natural killer (NK) cells, myeloid cells (including monocytes and macrophages), hematopoietic progenitors of myeloid cells and follicular dendritic cells. Anatomical reservoirs that may harbor latently HIV-infected cells include lymphoid tissues, the brain and the central nervous system, the gastrointestinal tract and the gut-associated lymphoid tissue (GALT), genital tract, lungs and skin. Tissues and cells found to harbor latently HIV infected cells and HIV reservoirs are described, e.g., in Kuo, et al., Curr Opin HIV AIDS. (2018) 13(2):137-142; Mzingwane, et al., Rev Med Virol. (2017) March; 27(2), doi: 10.1002/rmv.1924 (PMID 28128885); Churchill, et al., Nat Rev Microbiol. (2016) 14(1):55-60; Barton, et al., Trends Microbiol. (2016) 24(5):345-355, which are hereby incorporated herein by reference in their entireties for all purposes.

    [0105] In some embodiments, multiple biological samples are evaluated from a single patient. For example, in some embodiments two or more biological samples from two or more different tissues or two or more different anatomical reservoirs are evaluated from a single patient.

    Stage of Infection

    [0106] In various embodiments, the human subject is an adult, a juvenile or an infant. The subject may be symptomatic (e.g., viremic) or asymptomatic (e.g., acutely infected or ART suppressed). In some embodiments, the human subject is acutely infected or recently infected with HIV. In certain embodiments, the subject has not seroconverted. In some embodiments, the human subject is chronically infected with HIV. The subject many or may not be receiving a regimen of antiretroviral therapy (ART).

    [0107] Patients can be categorized into Fiebig stages I-VI, which are based on a sequential gain in positive HIV-1 clinical diagnostic assays (viral RNA measured by PCR, p24 and p31 viral antigens measured by enzyme-linked immunosorbent assay (ELISA). p24 antigen is a viral core protein that transiently appears in the blood during the ramp-up phase once HIV-1 RNA levels rise above 10,000 copies/mL and before the development of detectable HIV antibodies. In Fiebig stage I, during ramp-up viremia, only HIV-1 RNA in the blood can be detected. Fiebig stage II commences about 7 days later, when results of tests to detect p24 antigen become positive. In Fiebig stage III, within about 5 days after p24 antigen test results become positive, IgM anti-HIV-1 antibodies can be detected with sufficiently sensitive enzyme immunoassays (EIAs) (e.g., third-generation EIAs). Stage III typically occurs 1-2 weeks after the onset of acute retroviral symptoms. Fiebig stage IV represents the development of an indeterminate Western blot test and occurs about 3 days after EIA tests show positive results. Conversion to a clearly positive Western blot test, Fiebig stage V, generally occurs after another 7 days, or about 1 month after initial infection. Fiebig stages of HIV infection are described, e.g., in Fiebig, et al., AIDS. (2003) 17(13):1871-9; Cohen, et al., J Infect Dis. (2010) 202 Suppl 2:S270-7; and McMichael, et al., Nature Reviews Immunology (2010) 10:11-23, which are hereby incorporated herein by reference in their entireties for all purposes. In some embodiments, the biological sample evaluated is from a human subject having an HIV infection of Fiebig stage IV or earlier, e.g., Fiebig stage I, Fiebig stage II, Fiebig stage III or Fiebig stage IV. In some embodiments, the biological sample evaluated is from a human subject having an HIV infection of an HIV infection of Fiebig stage V or Fiebig stage VI.

    [0108] In some embodiments, the methods further comprise the step of obtaining the biological sample from the subject. In some embodiments, the methods entail receiving a report of the HIV gp120 amino acids residues present at the designated positions of interest, e.g., at 332 and 325, and one or more amino acid positions from the group consisting of: 63, 179, 320 and 330, wherein the amino acid positions are with reference to SEQ ID NO: 4.

    Determining gp120 Amino Acids of Interest

    [0109] Determination of the amino acid residues at HIV gp120 sequences of a subject at the designated positions of interest, e.g., at 332 and 325, and one or more amino acid positions from the group consisting of: 63, 179, 320 and 330, wherein the amino acid positions are with reference to SEQ ID NO: 4, can be done at the polynucleotide or polypeptide level. At the level of the polynucleotide, HIV RNA or proviral DNA isolated from one or more biological samples can be sequenced using methods known in the art. In some embodiments, HIV RNA or proviral DNA isolated from two or more biological samples of a subject are sequenced. In some embodiments, the two or more biological samples are obtained from different tissue sources (e.g., blood, peripheral blood mononuclear cells, lymph nodes and/or semen). In some embodiments, the two or more biological samples are obtained at different time points, e.g., 1, 2, 3, 4, 5, 6, 7 or 8 weeks apart, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months apart.

    [0110] As appropriate, primers that anneal to and amplify the HIV env coding sequence, and particularly the V3 variable region of gp120, can be used. In some embodiments, nested sets of primers can be used. In various embodiments, the RNA is sequenced directly or reverse-transcriptase polymerase chain reaction (RT-PCR) can be performed. In some embodiments, Sanger sequencing can be performed, e.g., when sequencing to determine amino acid residues in the V3 region, or when sequencing a sample from a patient in an early Fiebig stage of disease, e.g., prior to Fiebig stage III, e.g., Fiebig stages I or II. In various embodiments, single genome amplification (SGA) and sequencing is performed. Methods for single genome amplification (SGA) and sequencing of plasma HIV virion RNA, are described, e.g., in Salazar-Gonzalez, et al. (2008) J Virol 82:3952-3970; and Keele, et al., Proc Natl Acad Sci USA. (2008) 105(21):7552-7. Application of SGA to determining amino acid sequence variance in HIV gp120 sequences, and which can be employed in the herein described methods, is described, e.g., in Bar, et al., N Engl J Med. (2016) 375(21):2037-2050; and Mendoza, et al., Nature. (2018) 561(7724):479-484. In various embodiments, high throughput, Next Generation Sequencing (NGS), massively parallel or deep sequencing techniques are employed to sequence gp120, including at least the V3 variable region, from a population of HIV species in one or more biological samples from a single patient or subject. In such cases, multiple nucleic acid sequences encoding at least the V3 variable region of gp120 are sequenced and aligned. In some embodiments, the full-length of gp120 is sequenced. Illustrative platforms for performing NGS sequencing that can be used for determining the gp120 sequences of HIV species in one or more biological samples from a patient include Illumina (Solexa) (illumina.com), Ion torrent: Proton/PGM sequencing (thermofisher.com), SOLiD (thermofisher.com), and Single Molecule, Real-Time (SMRT) Sequencing (Pacific Biosciences, pacb.com). Methods for isolating and sequencing HIV gp120, including at least the V3 glycan region, from patients, and which can be applied in the present methods, are described in, e.g., Shioda, et al., J Virol. (1997) 71(7):4871-81; Coln, et al., J Virol Antivir Res. (2015) 4(3). pii: 143 (PMID: 27358904); Kafando, et al., PLoS One. (2017) 12(12):e0189999; Hebberecht, et al., PLoS One. (2018) 13(4):e0195679, Andrews, et al., Sci Rep. (2018) 8(1):5743 and Landais, et al. Immunity. (2017) 47(5):990-1003. As appropriate, shorter sequence reads of the nucleic acid sequences (contigs) can be assembled into longer sequences, including at least the V3 variable region of gp120. Methods of contig assembly of HIV genomic sequences that can be applied in the present methods are described, e.g., in Huang, et al., Bioinformation. (2018) 14(8):449-454; Hiener, et al., J Vis Exp. (2018) Oct. 16; (140). doi: 10.3791/58016; and Wymant, et al., Virus Evol. (2018) May 18; 4(1):vey007. doi: 10.1093/ve/vey007.

    [0111] In some embodiments, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%, of the sequenced V3 variable region of gp120 in a population of HIV obtained from one or more biological samples in a single patient comprise an amino acid sequence comprising a glycosylated asparagine at the position corresponding to amino acid residue position 332 (N332glycan), an aspartate at the position corresponding to amino acid residue position 325 (D325), and one or more of a threonine at the position corresponding to amino acid residue position 63 (T63), a leucine at the position corresponding to amino acid residue position 179 (L179), a threonine at the position corresponding to amino acid residue position 320 (T320), and a histidine at the position corresponding to amino acid residue position 330 (H330), wherein the amino acid positions are with reference to SEQ ID NO: 4. As used herein, numbering of a given amino acid polymer or nucleic acid polymer corresponds to, is corresponding to or is relative to the numbering of a selected or reference amino acid polymer or nucleic acid polymer when the position of any given polymer component (e.g., amino acid, nucleotide, also referred to generically as a residue) is designated by reference to the same or to an equivalent position (e.g., based on an optimal alignment or a consensus sequence) in the selected amino acid or nucleic acid polymer, rather than by the actual numerical position of the component in the given polymer. In some embodiments, HIV gp120 variants are detected to a frequency level about 1% (e.g., 1% mutant or variant frequency) of the virus population. In some embodiments, HIV gp120 variants are detected to a frequency level of about 0.5% of the virus population. As a rule of thumb, reliable detection of variants at 1% frequency will require HIV RNA levels of at least 1000 copies/mL. See, e.g., Casadell, et al., Virus Research 239 (2017) 69-81; Noguera-Julian, et al., J Infect Dis. (2017) 216 (suppl 9):S829-S833 and Lee, et al., Sci Rep. (2020) 10(1): 1634.

    [0112] 3. Administration of an Anti-HIV gp120 V3-Glycan Directed Antibody or Antigen-Binding Fragment Thereof

    [0113] In certain embodiments, the methods entail administration of an anti-HIV antibody or antigen-binding fragment thereof, or antigen binding molecule, that targets the V3 glycan binding region of gp120.

    [0114] HIV-1 is the main family of HIV and accounts for 95% of all infections worldwide. HIV-2 is mainly seen in a few West African countries.

    [0115] HIV viruses are divided into specific groups, M, N, O and P, of which M is the major group and responsible for majority of HIV/AIDS globally. Based on their genetic sequence, Group M is further subdivided into subtypes (also called clades) with prevalence in distinct geographical locations.

    [0116] A Group M subtype or clade is a subtype of HIV-1 group M defined by genetic sequence data. Examples of Group M subtypes include Subtypes A-K. Some of the subtypes are known to be more virulent or are resistant to different medications. There are also circulating recombinant forms or CRFs derived from recombination between viruses of different subtypes, which are each given a number. CRF12_BF, for example, is a recombination between subtypes B and F. Subtype A is common in West Africa. Subtype B is the dominant form in Europe, the Americas, Japan, Thailand, and Australia. Subtype C is the dominant form in Southern Africa, Eastern Africa, India, Nepal, and parts of China. Subtype D is generally only seen in Eastern and central Africa. Subtype E has never been identified as a nonrecombinant, only recombined with subtype A as CRF01_AE. Subtype F has been found in central Africa, South America and Eastern Europe. Subtype G (and the CRF02_AG) have been found in Africa and central Europe. Subtype H is limited to central Africa. Subtype I was originally used to describe a strain that is now accounted for as CRF04_cpx, with the cpx for a complex recombination of several subtypes. Subtype J is primarily found in North, Central and West Africa, and the Caribbean Subtype K is limited to the Democratic Republic of Congo and Cameroon. These subtypes are sometimes further split into sub-subtypes such as A1 and A2 or F1 and F2. In 2015, the strain CRF19, a recombinant of subtype A, subtype D, and subtype G, with a subtype D protease was found to be strongly associated with rapid progression to AIDS in Cuba.

    [0117] This disclosure provides, inter alia, methods entailing administration of human anti-HIV neutralizing antibodies (e.g., broadly neutralizing Abs) that target the V3-Glycan region of the gp120 polypeptide on the surface of HIV-infected cells. Neutralizing antibodies against viral envelope proteins provide adaptive immune defense against HIV-1 exposure by blocking the infection of susceptible cells. Broad neutralization indicates that the antibodies can neutralize HIV-1 isolates from different clades. Thus, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein have cross-clade binding activity.

    Antibodies and Antigen-Binding Fragments Thereof Directed to the V3 Glycan Region of HIV gp120

    [0118] In certain embodiments of the methods described herein, the subject is administered an antibody or antigen-binding fragment thereof, or an antigen-binding molecule that binds to HIV gp120 protein within the V3 Glycan region, e.g., an epitope or region of gp120 third variable loop (V3) and/or high mannose patch comprising a N332 oligomannose glycan. In certain embodiments, the administered antibody or antigen-binding fragment thereof, or an antigen-binding molecule binds to HIV-1 antigens expressed on a cell surface and eliminates or kills the infected cell.

    [0119] In certain embodiments, the administered antibody or antigen-binding fragment thereof, or an antigen-binding molecule, is or is derived from human neutralizing antibodies (e.g., monoclonal) that target HIV-1. A neutralizing antibody is one that can neutralize the ability of HIV to initiate and/or perpetuate an infection in a host and/or in target cells in vitro. The disclosure provides neutralizing monoclonal human antibodies, wherein the antibody recognizes an antigen from HIV, e.g., a gp120 polypeptide. In certain embodiments, a neutralizing antibody may inhibit the entry of HIV-1 virus, e.g., SF162 and/or JR-CSF, with a neutralization index>1.5 or >2.0 (Kostrikis L G et al., J. Virol., 70(1): 445-458 (1996)).

    [0120] In some embodiments, the administered antibody or antigen-binding fragment thereof, or an antigen-binding molecule, is or is derived from human broadly neutralizing antibodies (e.g., monoclonal) that target HIV-1. By broadly neutralizing antibodies are meant antibodies that neutralize more than one HIV-1 virus species (from diverse clades and different strains within a clade) in a neutralization assay. A broad neutralizing antibody may neutralize at least 2, 3, 4, 5, 6, 7, 8, 9 or more different strains of HIV-1, the strains belonging to the same or different clades. In particular embodiments, a broad neutralizing antibody may neutralize multiple HIV-1 species belonging to at least 2, 3, 4, 5, or 6 different clades. In certain embodiments, the inhibitory concentration of the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment may be less than about 0.0001 g/ml, less than about 0.001 g/ml, less than about 0.01 g/ml, less than about 0.1 g/ml, less than about 0.5 g/ml, less than about 1.0 g/ml, less than about 5 g/ml, less than about 10 g/ml, less than about 25 g/ml, less than about 50 g/ml, or less than about 100 g/ml to neutralize about 50% of the input virus in the neutralization assay.

    [0121] Illustrative broadly neutralizing antibodies that bind to gp120 in the third variable loop (V3) and/or high mannose patch comprising a N332 oligomannose glycan and which can be used in the herein described methods include without limitation GS-9722 (elipovimab), GS-9721, PGT-121, PGT-121.66, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, 10-1074-J, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03. Additional broadly neutralizing antibodies that bind to gp120 in the third variable loop (V3) and/or high mannose patch comprising a N332 oligomannose glycan and which can be used in the herein described methods are described, e.g., in WO 2012/030904; WO 2014/063059; WO 2016/149698; WO 2017/106346; WO 2018/075564, WO 2018/125813; WO 2018/237148, WO 2019/226829, WO 2020/023827, WO2020/056145 and Kerwin, et al., J Pharm Sci. 2020 January; 109(1):233-246, which are hereby incorporated herein by reference in their entireties for all purposes.

    [0122] Illustrative sequences of complementarity determining regions (CDRs) of the antibody or antigen-binding fragments, targeting HIV gp120 V3 glycan region, are provided in Tables A1-A4. Illustrative sequences of the VH and VL of the antibody or antigen-binding fragments, targeting HIV gp120 V3 glycan region, are provided in Table B.

    TABLE-US-00007 TABLEA1 CDRs(Kabat)forAnti-HIVgp120V3Glycan-DirectedAntibodiesorAntigen-BindingFragments Thereof Ab Name VH-CDR1 VH-CDR2 VH-CDR3 VL-CDR1 VL-CDR2 VL-CDR3 1 DSYWS YVHKSGDTNYSPSLKS TLHGRRIYGIVAFNEW GEKSLGSRAVQ NNQDRPS HIWDSRVPTK SEQIDNO:7 SEQIDNO:8 FTYFYMDV SEQID SEQID WV SEQIDNO:9 NO:10 NO:11 SEQID NO:12 2 DSYWS YVHKSGDTNYNPSLKS TLHGRRIYGIVAFNEW GEKSLGSRAVQ NNQDRPS HIWDSRVPTK SEQIDNO:7 SEQIDNO:13 FTYFYMDV SEQID SEQID WV SEQIDNO:9 NO:10 NO:11 SEQID NO:12 3 NYYWT YISDRESATYNPSLNS ARRGQRIYGVVSFGEF GRQALGSRAVQ NNQDRPS HMWDSRSGFS SEQID SEQIDNO:15 FYYYSMDV SEQID SEQID WS NO:14 SEQIDNO:16 NO:17 NO:11 SEQID NO:18 4 NYYWT YISDRETTTYNPSLNS ARRGQRIYGVVSFGEF GRQALGSRAVQ NNQDRPS HMWDSRSGFS SEQID SEQIDNO:19 FYYYYMDV SEQID SEQID WS NO:14 SEQIDNO:20 NO:17 NO:11 SEQID NO:18 5 GRFWS YFSDTDRSEYNPSLRS AQQGKRIYGIVSFGEF GERSRGSRAVQ NNQDRPA HYWDSRSPIS SEQID SEQIDNO:22 FYYYYMDA SEQID SEQID WI NO:21 SEQIDNO:23 NO:24 NO:25 SEQID NO:26 6 GRFWS YFSDTDRSEYNPSLRS AQQGKRIYGIVSFGEL GERSRGSRAVQ NNQDRPA HYWDSRSPIS SEQID SEQIDNO:22 FYYYYMDA SEQID SEQID WI NO:21 SEQIDNO:27 NO:24 NO:25 SEQID NO:26 7 DNYWS YVHDSGDTNYNPSLKS TKHGRRIYGVVAFKEW GEESLGSRSVI NNNDRPS HIWDSRRPTN SEQID SEQIDNO:29 FTYFYMDV SEQID SEQID WV NO:28 SEQIDNO:30 NO:31 NO:32 SEQID NO:33 8 DAYWS YVHHSGDTNYNPSLKR ALHGKRIYGIVALGEL GKESIGSRAVQ NNQDRPA HIYDARGGTN SEQID SEQIDNO:35 FTYFYMDV SEQID SEQID WV NO:34 SEQIDNO:36 NO:37 NO:25 SEQID NO:38 9 ACTYFWG SLSHCQSFWGSGWTFH FDGEVLVYNHWPKPAW NGTATNFVS GVDKRPP GSLVGNWDVI SEQID NPSLKS VDL SEQID SEQID SEQID NO:39 SEQIDNO:40 SEQIDNO:41 NO:42 NO:43 NO:44 10 ACDYFWG GLSHCAGYYNTGWTYH FDGEVLVYHDWPKPAW TGTSNRFVS GVNKRPS SSLVGNWDVI SEQID NPSLKS VDL SEQID SEQID SEQID NO:45 SEQIDNO:46 SEQIDNO:47 NO:48 NO:49 NO:50 11 ACDYFWG SLSHCAGYYNSGWTYH FGGDVLVYHDWPKPAW TGNINNFVS GVNKRPS GSLAGNWDVV SEQID NPSLKS VDL SEQID SEQID SEQID NO:45 SEQIDNO:51 SEQIDNO:52 NO:53 NO:49 NO:54 12 ACNSFWG SLSHCASYWNRGWTYH FGGEVLRYTDWPKPAW TGTSNNFVS DVNKRPS GSLVGNWDVI SEQID NPSLKS VDL SEQID SEQID SEQID NO:55 SEQIDNO:56 SEQIDNO:57 NO:58 NO:59 NO:44 13 GCDYFWG GLSHCAGYYNTGWTYH FDGEVLVYNDWPKPAW TGTSNNFVS GVNKRPS GSLVGNWDVI SEQID NPSLKS VDL SEQID SEQID SEQID NO:61 SEQIDNO:46 SEQIDNO:63 NO:58 NO:49 NO:44 14 TGHYYWG HIHYTTAVLHNPSLKS SGGDILYYYEWQKPHW NGTSSDIGGWN EVNKRPS SSLFGRWDVV SEQID SEQIDNO:65 FSP FVS SEQID SEQID NO:64 SEQIDNO:66 SEQID NO:68 NO:69 NO:67 15 GTDWGENDFHY SIHWRGRTTHYKTSFR HKYHDIFRVVPVAGWF RASQNVKNNLA DASSRAG QQYEEWPRT G S DP SEQID SEQID SEQID SEQID SEQIDNO:71 SEQIDNO:72 NO:73 NO:74 NO:75 NO:70 16 GGEWGDSDYHW SIHWRGTTHYNAPFRG HKYHDIVMVVPIAGWF RASQSVKNNLA DTSSRAS QQYEEWPRT G SEQIDNO:77 DP SEQID SEQID SEQID SEQID SEQIDNO:78 NO:79 NO:80 NO:75 NO:76 17 GGEWGDKDYHW SIHWRGTTHYKESLRR HRHHDVFMLVPIAGWF RASQNINKNLA ETYSKIA QQYEEWPRT G SEQIDNO:82 DV SEQID SEQID SEQID SEQID SEQIDNO:83 NO:84 NO:62 NO:75 NO:81 18 SDHSWT DIHYNGATTYNPSLRS NAIRIYGVVALGEWFH SGAPLTSRFTY RSSQRSS QSSDTSDSYK SEQID SEQIDNO:86 YGMDV SEQID SEQID M NO:85 SEQIDNO:87 NO:88 NO:89 SEQID NO:90 19 SDHSWT DVHYNGDNTYNPSLRG NVIRVFGVISLGEWFH SGPPLASRYTY RDRQFPS QSSDTSDSYK SEQID SEQIDNO:91 YGMDV SEQID SEQID M NO:85 SEQIDNO:92 NO:93 NO:94 SEQID NO:90 20 SDHSWT DVHYNGDTTYNPSLRG NVIRVFGVISLGEWFH SGPPLASRYTY RDRQFPS QSSDTSDSYK SEQID SEQIDNO:96 YGMDV SEQIDNO: SEQID M NO:85 SEQIDNO:92 93 NO:94 SEQID NO:90 21 SDHSWT DIHYNGATTYNPSLRS NAIRIYGVVALGEWFH SGAALTSRFTY RTSQRSS QSSDTSDSYK SEQID SEQIDNO:86 YGMDV SEQID SEQID M NO:85 SEQIDNO:87 NO:97 NO:98 SEQID NO:90 22 SDHSWT DIHYGGDITYNPSLRS NVIRVFGVIALGEWFH SGPPLASRYCY RDRQFSS QSSDINDSYK SEQID SEQIDNO:99 YGMDV SEQID SEQID M NO:85 SEQIDNO:100 NO:101 NO:102 SEQID NO:95 23 SDHSWT DIHYGGDITYNPSLRS NVIRVFGVIALGEWFH SGPPLASRYCY RDRQFSS QSSDTSDSFK SEQID SEQIDNO:99 YGMDV SEQID SEQID M NO:85 SEQIDNO:100 NO:101 NO:102 SEQID NO:103 24 SDHSWT DIHYGGDITYNPSLRS NVIRVFGVIALGEWFH SGPPLATRYCY RDRQFSS QSSDTSDSYK SEQID SEQIDNO:99 YGMDV SEQID SEQID M NO:85 SEQIDNO:100 NO:104 NO:102 SEQID NO:90 25 SDHSWT DIHYNGDKTYNPSLRG NVIRVFGVISLGEWFH SGPPLASRYTY RDRQFPS QSSDTSDSYK SEQID SEQIDNO:105 YGMDV SEQID SEQID M NO:85 SEQIDNO:92 NO:93 NO:94 SEQID NO:90 26 SDHSWT DIHYGGDITYNPSLRS NVIRVFGVIALGEWFH SGPPLASRYCY RDRQFSS QSSDNSDSFK SEQID SEQIDNO:99 YGMDV SEQID SEQID M NO:85 SEQIDNO:100 NO:101 NO:102 SEQID NO:107 27 DYAMA FMRGWAYGGSAQFAAF EQRNKDYRYGQEGFGY RASHFIANYVN ESSTLQR QQSHSPPVT SEQID AVG SYGMDV SEQID SEQID SEQID NO:108 SEQIDNO:109 SEQIDNO:110 NO:111 NO:112 NO:113 28 DYAMA FIRGWAYGQAAQYGKS EQRGGDGRYSGDGFGY RASHFIANYVN QSWTLNR QQSHSPPLS SEQID ASG PYGMDV SEQID SEQID SEQID NO:108 SEQIDNO:114 SEQIDNO:115 NO:111 NO:116 NO:117 29 DYAMA FIRGWAYGQSAQYGKS EQRGANGRYGGDGFGY RASHFIANYVN ESSTLNR QQSHSPPVS SEQID ASG SYGMDV SEQID SEQID SEQID NO:108 SEQIDNO:118 SEQIDNO:119 NO:111 NO:120 NO:121

    TABLE-US-00008 TABLEA2-CDRs(Chothia)forAnti-HIVgp120V3Glycan-DirectedAntibodiesorAntigen-Binding FragmentsThereof Ab Name VH-CDR1 VH-CDR2 VH-CDR3 VL-CDR1 VL-CDR2 VL-CDR3 30 GASISD YVHKSGDTN TLHGRRIYGIVAFNEWF GEKSLGSRAVQ NNQDRP HIWDSRVPTK SEQID SEQIDNO:124 TYFYMDV SEQIDNO:10 S WV NO:123 SEQIDNO:9 SEQID SEQID NO:11 NO:12 31 GDSMNN YISDRESAT ARRGQRIYGVVSFGEFF GRQALGSRAVQ NNQDRP HMWDSRSGFS SEQID SEQIDNO:126 YYYSMDV SEQIDNO:17 S WS NO:125 SEQIDNO:16 SEQID SEQID NO:11 NO:18 32 GGSISN YISDRETTT ARRGQRIYGVVSFGEFF GRQALGSRAVQ NNQDRP HMWDSRSGFS SEQID SEQIDNO:128 YYYYMDV SEQIDNO:17 S WS NO:127 SEQIDNO:20 SEQID SEQID NO:11 NO:18 33 NGSVSG YFSDTDRSE AQQGKRIYGIVSFGEFF GERSRGSRAVQ NNQDRP HYWDSRSPIS SEQID SEQIDNO:130 YYYYMDA SEQIDNO:24 A WI NO:129 SEQIDNO:23 SEQID SEQID NO:25 NO:26 34 NGSVSG YFSDTDRSE AQQGKRIYGIVSFGELF GERSRGSRAVQ NNQDRP HYWDSRSPIS SEQID SEQIDNO:130 YYYYMDA SEQIDNO:24 A WI NO:129 SEQIDNO:27 SEQID SEQID NO:25 NO:26 35 GTLVRD YVHDSGDTN TKHGRRIYGVVAFKEWF GEESLGSRSVI NNNDRP HIWDSRRPTN SEQID SEQIDNO:132 TYFYMDV SEQIDNO:31 S WV NO:131 SEQIDNO:30 SEQID SEQID NO:32 NO:33 36 GASIND YVHHSGDTN ALHGKRIYGIVALGELF GKESIGSRAVQ NNQDRP HIYDARGGTN SEQID SEQIDNO:134 TYFYMDV SEQIDNO:37 A WV NO:133 SEQIDNO:36 SEQID SEQID NO:25 NO:38 37 GESTGACT SLSHCQSFWGSGW FDGEVLVYNHWPKPAWV NGTATNFVS GVDKRP GSLVGNWDVI SEQID TF DL SEQIDNO:42 P SEQID NO:135 SEQIDNO:136 SEQIDNO:41 SEQID NO:44 NO:43 38 GDSTAACD GLSHCAGYYNTGW FDGEVLVYHDWPKPAWV TGTSNRFVS GVNKRP SSLVGNWDVI SEQID TY DL SEQIDNO:48 S SEQID NO:137 SEQIDNO:138 SEQIDNO:47 SEQID NO:50 NO:49 39 GDSTAACD SLSHCAGYYNSGW FGGDVLVYHDWPKPAWV TGNINNFVS GVNKRP GSLAGNWDVV SEQID TY DL SEQIDNO:53 S SEQID NO:137 SEQIDNO:106 SEQIDNO:52 SEQID NO:54 NO:49 40 GDSTAACN SLSHCASYWNRGW FGGEVLRYTDWPKPAWV TGTSNNFVS DVNKRP GSLVGNWDVI SEQID TYHNPSLKS DL SEQIDNO:58 S SEQID NO:139 SEQIDNO:56 SEQIDNO:57 SEQID NO:44 NO:59 41 GDSTAGCD GLSHCAGYYNTGW FDGEVLVYNDWPKPAWV TGTSNNFVS GVNKRP GSLVGNWDVI SEQID TY DL SEQIDNO:58 S SEQID NO:141 SEQIDNO:138 SEQIDNO:63 SEQID NO:44 NO:49 42 GESINTGH HIHYTTAVL SGGDILYYYEWQKPHWF NGTSSDIGGWNF EVNKRP SSLFGRWDVV SEQID SEQIDNO:143 SP VS S SEQID NO:142 SEQIDNO:66 SEQIDNO:67 SEQID NO:69 NO:68 43 GGSMRGTDWGEN SIHWRGRTTH HKYHDIFRVVPVAGWFD RASQNVKNNLA DASSRA QQYEEWPRT D SEQIDNO:145 P SEQIDNO:73 G SEQID SEQID SEQIDNO:72 SEQID NO:75 NO:144 NO:74 44 GGSIRGGEWGDS SIHWRGTTH HKYHDIVMVVPIAGWFD RASQSVKNNLA DTSSRA QQYEEWPRT D SEQIDNO:147 P SEQIDNO:79 S SEQID SEQID SEQIDNO:78 SEQID NO:75 NO:146 NO:80 45 GDSIRGGEWGDK SIHWRGTTH HRHHDVFMLVPIAGWFD RASQNINKNLA ETYSKI QQYEEWPRT D SEQIDNO:147 V SEQIDNO:84 A SEQID SEQID SEQIDNO:83 SEQID NO:75 NO:148 NO:62 46 QDSRPSDH HYNGA NAIRIYGVVALGEWFHY SGAPLTSRFTY RSSQRS QSSDTSDSYK SEQID SEQIDNO:150 GMDV SEQIDNO:88 S M NO:149 SEQIDNO:87 SEQID SEQID NO:89 NO:90 47 NDSRPSDH HYNGA NAIRIYGVVALGEWFHY SGAPLTSRFTY RSSQRS QSSDTSDSYK SEQID SEQIDNO:150 GMDV SEQIDNO:88 S M NO:151 SEQIDNO:87 SEQID SEQID NO:89 NO:90 48 GDSRPSDH HYNGD NVIRVFGVISLGEWFHY SGPPLASRYTY RDRQFP QSSDTSDSYK SEQID SEQIDNO:153 GMDV SEQIDNO:93 S M NO:152 SEQIDNO:92 SEQID SEQID NO:94 NO:90 49 NDSRPSDH HYNGA NAIRIYGVVALGEWFHY SGAALTSRFTY RTSQRS QSSDTSDSYK SEQID SEQIDNO:150 GMDV SEQIDNO:97 S M NO:151 SEQIDNO:87 SEQID SEQID NO:98 NO:90 50 GDSRPSDH HYGGD NVIRVFGVIALGEWFHY SGPPLASRYCY RDRQFS QSSDINDSYK SEQID SEQIDNO:122 GMDV SEQID S M NO:152 SEQIDNO:100 NO:101 SEQID SEQID NO:102 NO:95 51 GDSRPSDH HYGGD NVIRVFGVIALGEWFHY SGPPLASRYCY RDRQFS QSSDTSDSFK SEQID SEQIDNO:122 GMDV SEQID S M NO:152 SEQIDNO:100 NO:101 SEQID SEQID NO:102 NO:103 52 GDSRPSDH HYGGD NVIRVFGVIALGEWFHY SGPPLATRYCY RDRQFS QSSDTSDSYK SEQID SEQIDNO:122 GMDV SEQID S M NO:152 SEQIDNO:100 NO:104 SEQID SEQID NO:102 NO:90 53 GDSRPSDH HYGGD NVIRVFGVIALGEWFHY SGPPLASRYCY RDRQFS QSSDNSDSFK SEQID SEQIDNO:122 GMDV SEQID S M NO:152 SEQIDNO:100 NO:101 SEQID SEQID NO:102 NO:107 54 GFYFPDY RGWAYGGS EQRNKDYRYGQEGFGYS RASHFIANYVN ESSTLQ QQSHSPPVT SEQID SEQIDNO:155 YGMDV SEQID R SEQID NO:154 SEQIDNO:110 NO:111 SEQID NO:113 NO:112 55 DFYFPDY RGWAYGQA EQRGGDGRYSGDGFGYP RASHFIANYVN QSWTLN QQSHSPPLS SEQID SEQIDNO:157 YGMDV SEQID R SEQID NO:156 SEQIDNO:115 NO:111 SEQID NO:117 NO:116 56 DFYFPDY RGWAYGQS EQRGANGRYGGDGFGYS RASHFIANYVN ESSTLN QQSHSPPVS SEQID SEQIDNO:159 YGMDV SEQID R SEQID NO:158 SEQIDNO:119 NO:111 SEQID NO:121 NO:120

    TABLE-US-00009 TABLEA3 CDRs(IMGT)forAnti-HIVgp120V3Glycan-DirectedAntibodiesorAntigen-BindingFragments Thereof Ab Name VH-CDR1 VH-CDR2 VH-CDR3 VL-CDR1 VL-CDR2 VL-CDR3 57 GASISDSY VHKSGDT ARTLHGRRIYGIVAFNEWFTYFYM SLGSRA NNQ HIWDSRVPTKW SEQID SEQID DV SEQID SEQID V NO:160 NO:161 SEQIDNO:162 NO:163 NO:164 SEQID NO:12 58 GDSMNNYY ISDRESA ATARRGQRIYGVVSFGEFFYYYSM ALGSRA NNQ HMWDSRSGFSW SEQID SEQID DV SEQID SEQID S NO:165 NO:166 SEQIDNO:167 NO:168 NO:164 SEQID NO:18 180 GDSMNNYY ISDRESA ARARRGQRIYGVVSFGEFFYYYSM ALGSRA NNQ HMWDSRSGFSW SEQID SEQID DV SEQID SEQID S NO:165 NO:166 SEQIDNO:461 NO:168 NO:164 SEQID NO:18 59 GGSISNYY ISDRETT ATARRGQRIYGVVSFGEFFYYYYM ALGSRA NNQ HMWDSRSGFSW SEQID SEQID DV SEQID SEQID S NO:169 NO:170 SEQIDNO:171 NO:168 NO:164 SEQID NO:18 60 NGSVSGRF FSDTDRS ARAQQGKRIYGIVSFGELFYYYYM SRGSRA NNQ HYWDSRSPISW SEQID SEQID DA SEQID SEQID I NO:172 NO:173 SEQIDNO:174 NO:175 NO:164 SEQID NO:26 61 NGSVSGRF FSDTDRS ARAQQGKRIYGIVSFGEFFYYYYM SRGSRA NNQ HYWDSRSPISW SEQID SEQID DA SEQID SEQID I NO:172 NO:173 SEQIDNO:176 NO:175 NO:164 SEQID NO:26 62 GTLVRDNY VHDSGDT ATTKHGRRIYGVVAFKEWFTYFYM SIGSRA NNQ HIYDARGGTNW SEQID SEQID DV SEQID SEQID V NO:177 NO:178 SEQIDNO:179 NO:180 NO:164 SEQID NO:38 63 GASINDAY VHHSGDT ARALHGKRIYGIVALGELFTYFYM SLGSRS NNN HIWDSRRPTNW SEQID SEQID DV SEQID SEQID V NO:181 NO:182 SEQIDNO:183 NO:184 NO:185 SEQID NO:33 64 GESTGACTY LSHCQSFWGSGW ARFDGEVLVYNHWPKPAWVDL ATNF GVD GSLVGNWDVI F T SEQIDNO:188 SEQID SEQID SEQID SEQID SEQID NO:189 NO:190 NO:44 NO:186 NO:187 65 GDSTAACDY LSHCAGYYNTGW ARFDGEVLVYHDWPKPAWVDL SNRF GVN SSLVGNWDVI F T SEQIDNO:193 SEQID SEQID SEQID SEQID SEQID NO:194 NO:195 NO:50 NO:191 NO:192 66 GDSTAACDY LSHCAGYYNSGW ARFGGDVLVYHDWPKPAWVDL INNF GVN GSLAGNWDVV F T SEQIDNO:197 SEQID SEQID SEQID SEQID SEQID NO:198 NO:195 NO:54 NO:191 NO:196 67 GDSTAACNS LSHCASYWNRGW ARFGGEVLRYTDWPKPAWVDL SNNF DVN GSLVGNWDVI F T SEQIDNO:201 SEQID SEQID SEQID SEQID SEQID NO:202 NO:399 NO:44 NO:199 NO:200 68 GDSTAGCDY LSHCAGYYNTGW ARFDGEVLVYNDWPKPAWVDL SNNF GVN GSLVGNWDVI F T SEQIDNO:205 SEQID SEQID SEQID SEQID SEQID NO:202 NO:195 NO:44 NO:203 NO:204 69 GESINTGHY IHYTTAV VRSGGDILYYYEWQKPHWFSP SSDIGGWNF EVN SSLFGRWDVV Y SEQID SEQIDNO:208 SEQID SEQID SEQID SEQID NO:207 NO:209 NO:210 NO:69 NO:206 70 GGSMRGTDW IHWRGRTT ARHKYHDIFRVVPVAGWFDP QNVKNN DAS QQYEEWPRT GENDFH SEQID SEQIDNO:213 SEQID SEQID SEQID SEQID NO:212 NO:214 NO:215 NO:75 NO:211 71 GGSIRGGEW IHWRGTT VKHKYHDIVMVVPIAGWFDP QSVKNN DTS QQYEEWPRT GDSDYH SEQID SEQIDNO:218 SEQID SEQID SEQID SEQID NO:217 NO:219 NO:220 NO:75 NO:216 72 GDSIRGGEW IHWRGTT ARHRHHDVFMLVPIAGWFDV QNINKN ETY QQYEEWPRT GDKDYH SEQID SEQIDNO:60 SEQID SEQID SEQID SEQID NO:217 NO:223 NO:224 NO:75 NO:221 73 QDSRPSDHS IHYNGAT NAIRIYGVVALGEWFHYGMDV PLTSRF RSS QSSDTSDSYKM SEQID SEQID SEQIDNO:87 SEQID SEQID SEQID NO:225 NO:226 NO:227 NO:228 NO:90 74 NDSRPSDHS IHYNGAT NAIRIYGVVALGEWFHYGMDV PLTSRF RSS QSSDTSDSYKM SEQID SEQID SEQIDNO:87 SEQID SEQID SEQID NO:229 NO:226 NO:227 NO:228 NO:90 75 GDSRPSDHS VHYNGDN NVIRVFGVISLGEWFHYGMDV PLASRY RDR QSSDTSDSYKM SEQID SEQID SEQIDNO:92 SEQID SEQID SEQID NO:230 NO:231 NO:232 NO:233 NO:90 76 GDSRPSDHS VHYNGDT NVIRVFGVISLGEWFHYGMDV PLASRY RDR QSSDTSDSYKM SEQID SEQID SEQIDNO:92 SEQID SEQID SEQID NO:230 NO:234 NO:232 NO:233 NO:90 77 NDSRPSDHS IHYNGAT NAIRIYGVVALGEWFHYGMDV ALTSRF RTS QSSDTSDSYKM SEQID SEQID SEQIDNO:87 SEQID SEQID SEQID NO:229 NO:226 NO:235 NO:398 NO:90 78 GDSRPSDHS IHYGGDI NVIRVFGVIALGEWFHYGMDV PLASRY RDR QSSDINDSYKM SEQID SEQID SEQIDNO:100 SEQID SEQID SEQID NO:230 NO:236 NO:232 NO:233 NO:95 79 GDSRPSDHS IHYGGDI NVIRVFGVIALGEWFHYGMDV PLASRY RDR QSSDTSDSFKM SEQID SEQID SEQIDNO:100 SEQID SEQID SEQID NO:230 NO:236 NO:232 NO:233 NO:103 80 GDSRPSDHS IHYGGDI NVIRVFGVIALGEWFHYGMDV PLATRY RDR QSSDTSDSYKM SEQID SEQID SEQIDNO:100 SEQID SEQID SEQID NO:230 NO:236 NO:237 NO:233 NO:90 81 GDSRPSDHS IHYNGDK NVIRVFGVISLGEWFHYGMDV PLASRY RDR QSSDTSDSYKM SEQID SEQID SEQIDNO:92 SEQID SEQID SEQID NO:230 NO:238 NO:232 NO:233 NO:90 82 GDSRPSDHS IHYGGDI NVIRVFGVIALGEWFHYGMDV PLASRY RDR QSSDNSDSFKM SEQID SEQID SEQIDNO:100 SEQID SEQID SEQID NO:230 NO:236 NO:232 NO:233 NO:107 83 GFYFPDYA MRGWAYGGSA EQRNKDYRYGQEGFGYSYGMDV HFIANY ESS QQSHSPPVT SEQID SEQID SEQIDNO:110 SEQID SEQID SEQID NO:239 NO:240 NO:241 NO:242 NO:113 84 DFYFPDYA IRGWAYGQAA EQRGGDGRYSGDGFGYPYGMDV HFIANY QSW QQSHSPPLS SEQID SEQID SEQIDNO:115 SEQID SEQID SEQID NO:243 NO:244 NO:241 NO:245 NO:117 85 DFYFPDYA IRGWAYGQSA EQRGANGRYGGDGFGYSYGMDV HFIANY ESS QQSHSPPVS SEQID SEQID SEQIDNO:119 SEQID SEQID SEQID NO:243 NO:246 NO:241 NO:247 NO:121

    TABLE-US-00010 TABLEA4 CDRs(Honegger)forAnti-HIVgp120V3Glycan-DirectedAntibodiesorAntigen-BindingFragments Thereof Ab Name VH-CDR1 VH-CDR2 VH-CDR3 VL-CDR1 VL-CDR2 VL-CDR3 86 VSGASISDSY VHKSGDTNYSPSLKS TLHGRRIYGIV EKSLGSRA NNQDRPSGIPER WDSRVPTKW SEQID R AFNEWFTYFYM SEQID SEQID SEQID NO:248 SEQIDNO:249 D NO:251 NO:252 NO:253 SEQID NO:250 87 VSGASISDSY VHKSGDTNYNPSLKS TLHGRRIYGIV EKSLGSRA NNQDRPSGIPER WDSRVPTKW SEQID R AFNEWFTYFYM SEQID SEQID SEQID NO:248 SEQIDNO:254 D NO:251 NO:252 NO:253 SEQID NO:250 88 VSGDSMNNYY ISDRESATYNPSLNS ARRGQRIYGVV RQALGSRA NNQDRPSGIPER WDSRSGFSW SEQID R SFGEFFYYYSM SEQID SEQID SEQID NO:255 SEQIDNO:256 D NO:258 NO:252 NO:259 SEQID NO:257 89 VSGGSISNYY ISDRETTTYNPSLNS ARRGQRIYGVV RQALGSRA NNQDRPSGIPER WDSRSGFSW SEQID R SFGEFFYYYYM SEQID SEQID SEQID NO:260 SEQIDNO:261 D NO:258 NO:252 NO:259 SEQID NO:262 90 VSNGSVSGRF FSDTDRSEYNPSLRS AQQGKRIYGIV ERSRGSRA NNQDRPAGVSER WDSRSPISW SEQID R SFGELFYYYYM SEQID SEQID SEQID NO:263 SEQIDNO:264 D NO:266 NO:267 NO:268 SEQID NO:265 91 VSNGSVSGRF FSDTDRSEYNPSLRS AQQGKRIYGIV ERSRGSRA NNQDRPAGVSER WDSRSPISW SEQID R SFGEFFYYYYM SEQID SEQID SEQID NO:263 SEQIDNO:264 D NO:266 NO:267 NO:268 SEQID NO:397 92 VSGASINDAY VHHSGDTNYNPSLKR ALHGKRIYGIV KESIGSRA NNQDRPAGVPER YDARGGTNW SEQID R ALGELFTYFYM SEQID SEQID SEQID NO:269 SEQIDNO:270 D NO:272 NO:273 NO:274 SEQID NO:271 93 VSGTLVRDNY VHDSGDTNYNPSLKS TKHGRRIYGVV EESLGSRS NNNDRPSGIPDR WDSRRPTNW SEQID R AFKEWFTYFYM SEQID SEQID SEQID NO:275 SEQIDNO:276 D NO:278 NO:279 NO:280 SEQID NO:277 94 VSGESTGACTYF LSHCQSFWGSGWTFH FDGEVLVYNHW GTATNF GVDKRPPGVPDR LVGNWDV SEQID NPSLKSR PKPAWVD SEQID SEQID SEQID NO:281 SEQIDNO:282 SEQID NO:284 NO:285 NO:286 NO:283 95 VSGDSTAACDYF LSHCAGYYNTGWTYH FDGEVLVYHDW GTSNRF GVNKRPSGVPDR LVGNWDV SEQID NPSLKSR PKPAWVD SEQID SEQID SEQID NO:287 SEQIDNO:288 SEQID NO:290 NO:291 NO:286 NO:289 96 VSGDSTAACDYF LSHCAGYYNSGWTYH FGGDVLVYHDW GNINNF GVNKRPSGVPDR LAGNWDV SEQID NPSLKSR PKPAWVD SEQID SEQID SEQID NO:287 SEQIDNO:292 SEQID NO:294 NO:295 NO:296 NO:293 97 VSGDSTAACNSF LSHCASYWNRGWTYH FGGEVLRYTDW GTSNNF DVNKRPSGVPDR LVGNWDV SEQID NPSLKSR PKPAWVD SEQID SEQID SEQID NO:297 SEQIDNO:298 SEQID NO:300 NO:301 NO:286 NO:299 98 VSGDSTAGCDYF LSHCAGYYNTGWTYH FDGEVLVYNDW GTSNNF GVNKRPSGVPDR LVGNWDV SEQID NPSLKSR PKPAWVD SEQID SEQID SEQID NO:302 SEQIDNO:288 SEQID NO:300 NO:295 NO:286 NO:303 99 VSGESINTGHYY IHYTTAVLHNPSLKS SGGDILYYYEW GTSSDIGGWN EVNKRPSGVPGR LFGRWDV SEQID R QKPHWFS F SEQID SEQID NO:304 SEQIDNO:305 SEQID SEQID NO:308 NO:309 NO:306 NO:307 100 VSGGSMRGTDWG IHWRGRITHYKTSFR HKYHDIFRVVP ASQNVKNN DASSRAGGIPDR YEEWPR ENDFH SR VAGWFD SEQID SEQID SEQID SEQID SEQIDNO:311 SEQID NO:313 NO:314 NO:315 NO:310 NO:312 101 ASGGSIRGGEWG IHWRGTTHYNAPFRG HKYHDIVMVVP ASQSVKNN DTSSRASGIPAR YEEWPR DSDYH R IAGWFD SEQID SEQID SEQID SEQID SEQIDNO:317 SEQID NO:319 NO:320 NO:315 NO:316 NO:318 102 VSGDSIRGGEWG IHWRGTTHYKESLRR HRHHDVFMLVP ASQNINKN ETYSKIAAFPAR YEEWPR DKDYH R IAGWFD SEQID SEQID SEQID SEQID SEQIDNO:322 SEQID NO:324 NO:325 NO:315 NO:321 NO:323 103 VSQDSRPSDHS IHYNGATTYNPSLRS NAIRIYGVVAL GAPLTSRF RSSQRSSGWSGR SDTSDSYK SEQID R GEWFHYGMD SEQID SEQID SEQID NO:326 SEQIDNO:327 SEQID NO:329 NO:330 NO:331 NO:328 104 VSNDSRPSDHS IHYNGATTYNPSLRS NAIRIYGVVAL GAPLTSRF RSSQRSSGWSGR SDTSDSYK SEQID R GEWFHYGMD SEQID SEQID SEQID NO:332 SEQIDNO:327 SEQID NO:329 NO:330 NO:331 NO:328 105 VFGDSRPSDHS VHYNGDNTYNPSLRG NVIRVFGVISL GPPLASRY RDRQFPSGVSGR SDTSDSYK SEQID R GEWFHYGMD SEQID SEQID SEQID NO:333 SEQIDNO:334 SEQID NO:336 NO:337 NO:338 NO:335 106 VFGDSRPSDHS VHYNGDTTYNPSLRG NVIRVFGVISL GPPLASRY RDRQFPSGVSGR SDTSDSYK SEQID R GEWFHYGMD SEQID SEQID SEQID NO:333 SEQIDNO:339 SEQID NO:336 NO:337 NO:338 NO:335 107 VSNDSRPSDHS IHYNGATTYNPSLRS NAIRIYGVVAL GAALTSRF RTSQRSSGWSGR SDTSDSYK SEQID R GEWFHYGMD SEQID SEQID SEQID NO:332 SEQIDNO:327 SEQID NO:340 NO:341 NO:338 NO:328 108 ISGDSRPSDHS IHYGGDITYNPSLRS NVIRVFGVIAL GPPLASRY RDRQFSSGMSGR SDINDSYK SEQID R GEWFHYGMD SEQID SEQID SEQID NO:342 SEQIDNO:343 SEQID NO:336 NO:345 NO:346 NO:344 109 ISGDSRPSDHS IHYGGDITYNPSLRS NVIRVFGVIAL GPPLASRY RDRQFSSGISGR SDTSDSFK SEQID R GEWFHYGMD SEQID SEQID SEQID NO:342 SEQIDNO:343 SEQID NO:336 NO:347 NO:348 NO:344 110 ISGDSRPSDHS IHYGGDITYNPSLRS NVIRVFGVIAL GPPLATRY RDRQFSSGVSGR SDTSDSYK SEQID R GEWFHYGMD SEQID SEQID SEQID NO:342 SEQIDNO:343 SEQID NO:349 NO:350 NO:338 NO:344 111 VFGDSRPSDHS IHYNGDKTYNPSLRG NVIRVFGVISL GPPLASRY RDRQFPSGVSGR SDTSDSYK SEQID R GEWFHYGMD SEQID SEQID SEQID NO:333 SEQIDNO:351 SEQID NO:336 NO:337 NO:338 NO:335 112 ISGDSRPSDHS IHYGGDITYNPSLRS NVIRVFGVIAL GPPLASRY RDRQFSSGISGR SDNSDSFK SEQID R GEWFHYGMD SEQID SEQID SEQID NO:342 SEQIDNO:343 SEQID NO:336 NO:347 NO:352 NO:344 113 ASGFYFPDYA MRGWAYGGSAQFAAF EQRNKDYRYGQ ASHFIANY ESSTLQRGVPSR SHSPPV SEQID AVGK EGFGYSYGMD SEQID SEQID SEQID NO:353 SEQIDNO:354 SEQID NO:356 NO:357 NO:358 NO:355 114 AFDFYFPDYA IRGWAYGQAAQYGKS EQRGGDGRYSG ASHFIANY QSWTLNRGIPSR SHSPPL SEQID ASGR DGFGYPYGMD SEQID SEQID SEQID NO:359 SEQIDNO:360 SEQID NO:356 NO:362 NO:363 NO:361 115 AFDFYFPDYA IRGWAYGQSAQYGKS EQRGANGRYGG ASHFIANY ESSTLNRGVPSR SHSPPV SEQID ASGR DGFGYSYGMD SEQID SEQID SEQID NO:359 SEQIDNO:364 SEQID NO:356 NO:366 NO:358 NO:365

    TABLE-US-00011 TABLEB VH/VLforAnti-HIVgp120V3Glycan-DirectedAntibodiesorAntigen-BindingFragments Thereof SEQ SEQ Ab ID ID Name NO VH NO VL 150 400 QMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWI 401 SDISVAPGETARISCGEKSLGSRAVQWYQHRA RRSPGKGLEWIGYVHKSGDTNYSPSLKSRVNLSLDTS GQAPSLIIYNNQDRPSGIPERFSGSPDSPFGT KNQVSLSLVAATAADSGKYYCARTLHGRRIYGIVAFN TATLTITSVEAGDEADYYCHIWDSRVPTKWVF EWFTYFYMDVWGNGTQVTVSS GGGTTLTVL 151 402 QMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWI 403 SDISVAPGETARISCGEKSLGSRAVQWYQHRA RRSPGKGLEWIGYVHKSGDTNYNPSLKSRVHLSLDTS GQAPSLIIYNNQDRPSGIPERFSGSPDFRPGT KNQVSLSLTGVTAADSGKYYCARTLHGRRIYGIVAFN TATLTITSVEAGDEADYYCHIWDSRVPTKWVF EWFTYFYMDVWGTGTQVTVSS GGGTTLTVL 181 462 QMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWI 463 SDISVAPGETARISCGEKSLGSRAVQWYQHRA RRSPGKGLEWIGYVHKSGDTNYNPSLKSRVHLSLDTS GQAPSLIIYNNQDRPSGIPERFSGSPDSRPGT KNQVSLSLTGVTAADSGKYYCARTLHGRRIYGIVAFN TATLTITSVEAGDEADYYCHIWDSRVPTKWVF EWFTYFYMDVWGTGTQVTVSS GGGTTLTVL 182 464 QMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWI 465 SDISVAPGETARISCGEKSLGSRAVQWYQQRA RQPPGKGLEWIGYVHKSGDTNYSPSLKSRVNLSLDTS GQAPSLIIYNNQDRPSGIPERFSGSPDSGFGT KNQVSLSLSAATAADSGVYYCARTLHGRRIYGIVAFN TATLTITSVEAGDEADYYCHIWDSRVPTKWVF EWFTYFYMDVWGNGTQVTVSS GGGTTLTVL 152 402 QMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWI 404 SDISVAPGETARISCGEKSLGSRAVQWYQHRA RRSPGKGLEWIGYVHKSGDTNYNPSLKSRVHLSLDTS GQAPSLIIYNNQDRPSGIPERFSGSPDSRPGT KNQVSLSLTGVTAADSGKYYCARTLHGRRIYGIVAFN TATLTITSVEAGDEADYYCHIWDSRVPTKWVF EWFTYFYMDVWGTGTQVTVSS GGGTTLTVL 153 405 QVQLQESGPGLVKPSETLSVTCSVSGDSMNNYYWTWI 406 SYVRPLSVALGETARISCGRQALGSRAVQWYQ RQSPGKGLEWIGYISDRESATYNPSLNSRVVISRDTS HRPGQAPILLIYNNQDRPSGIPERFSGTPDIN KNQLSLKLNSVTPADTAVYYCATARRGQRIYGVVSFG FGTRATLTISGVEAGDEADYYCHMWDSRSGFS EFFYYYSMDVWGKGTTVTVSS WSFGGATRLTVL 183 466 QVQLQESGPGLVKPSETLSVTCSVSGDSMNNYYWTWI 467 SPVRPLSVALGETARISCGRQALGSRAVQWYQ RQSPGKGLEWIGYISDRESATYNPSLNSRVTISRDTS HRPGQAPILLIYNNQDRPSGIPERFSGTPDIN KNQFSLKLNSVTPADTAVYYCARARRGQRIYGVVSFG FGTRATLTISGVEAGDEADYYCHMWDSRSGFS EFFYYYSMDVWGKGTTVTVSS WSFGGATRLTVL 154 407 QVQLQESGPGLVRPSETLSVICIVSGGSISNYYWTWI 408 SYVSPLSVALGETARISCGRQALGSRAVQWYQ RQSPGKGLEWIGYISDRETTTYNPSLNSRAVISRDTS HKPGQAPILLIYNNQDRPSGIPERFSGTPDIN KNQLSLQLRSVTTADTAIYFCATARRGQRIYGVVSFG FGTTATLTISGVEVGDEADYYCHMWDSRSGFS EFFYYYYMDVWGKGTAVTVSS WSFGGATRLTV 155 409 QVHLQESGPGLVTPSETLSLICTVSNGSVSGRFWSWI 410 SLNPLSLAPGATAKIPCGERSRGSRAVQWYQQ RQSPGRGLEWIGYFSDTDRSEYNPSLRSRLTLSVDRS KPGQAPTLIIYNNQDRPAGVSERFSGNPDVAI KNQLSLRLKSVTAADSATYYCARAQQGKRIYGIVSFG GVTATLTISRVEVGDEADYYCHYWDSRSPISW EFFYYYYMDAWGKGTPVTVSS IFGGGTQLTVL 156 411 QVHLQESGPGLVTPSETLSLICTVSNGSVSGRFWSWI 412 SLNPLSLAPGATAKIPCGERSRGSRAVQWYQQ RQSPGRGLEWIGYFSDTDRSEYNPSLRSRLTLSVDRS KPGQAPTLIIYNNQDRPAGVSERFSGNPDVAI KNQLSLKLKSVTAADSATYYCARAQQGKRIYGIVSFG GVTATLTISRVEVGDEGDYYCHYWDSRSPISW ELFYYYYMDAWGKGTPVTVSS IFAGGTQLTVL 157 413 QVHLQESGPGLVKPSETLSLTCNVSGTLVRDNYWSWI 414 TFVSVAPGQTARITCGEESLGSRSVIWYQQRP RQPLGKQPEWIGYVHDSGDTNYNPSLKSRVHLSLDKS GQAPSLIIYNNNDRPSGIPDRFSGSPGSTFGT KNLVSLRLTGVTAADSAIYYCATTKHGRRIYGVVAFK TATLTITSVEAGDEADYYCHIWDSRRPTNWVF EWFTYFYMDVWGKGTSVTVSS GEGTTLIVL 158 415 QLHLQESGPGLVKPPETLSLTCSVSGASINDAYWSWI 416 SSMSVSPGETAKISCGKESIGSRAVQWYQQKP RQSPGKRPEWVGYVHHSGDTNYNPSLKRRVTFSLDTA GQPPSLIIYNNQDRPAGVPERFSASPDFRPGT KNEVSLKLVDLTAADSATYFCARALHGKRIYGIVALG TATLTITNVDAEDEADYYCHIYDARGGTNWVF ELFTYFYMDVWGKGTAVTVSS DRGTTLTVL 159 417 QSQLQESGPRLVEASETLSLTCNVSGESTGACTYFWG 418 QSALTQPPSASGSPGQSITISCNGTATNFVSW WVRQAPGKGLEWIGSLSHCQSFWGSGWTFHNPSLKSR YQQFPDKAPKLIIFGVDKRPPGVPDRFSGSRS LTISLDTPKNQVFLKLTSLTAADTATYYCARFDGEVL GTTASLTVSRLQTDDEAVYYCGSLVGNWDVIF VYNHWPKPAWVDLWGRGIPVTVSS GGGTTLTVL 160 419 QPQLQESGPGLVEASETLSLTCTVSGDSTAACDYFWG 420 QSALTQPPSASGSPGQSISISCTGTSNRFVSW WVRQPPGKGLEWIGGLSHCAGYYNTGWTYHNPSLKSR YQQHPGKAPKLVIYGVNKRPSGVPDRFSGSKS LTISLDTPKNQVFLKLNSVTAADTAIYYCARFDGEVL GNTASLTVSGLQTDDEAVYYCSSLVGNWDVIF VYHDWPKPAWVDLWGRGTLVTVSS GGGTKLTVL 161 421 QLQMQESGPGLVKPSETLSLSCTVSGDSIRGGEWGDK 422 EIVMTQSPDTLSVSPGETVTLSCRASQNINKN DYHWGWVRHSAGKGLEWIGSIHWRGITHYKESLRRRV LAWYQYKPGQSPRLVIFETYSKIAAFPARFVA SMSIDTSRNWFSLRLASVTAADTAVYFCARHRHHDVF SGSGTEFTLTINNMQSEDVAVYYCQQYEEWPR MLVPIAGWFDVWGPGVQVTVSS TFGQGTKVDIK 162 423 QLQLQESGPGLVKPSETLSLICTVSGGSMRGTDWGEN 424 EIVMTQSPPTLSVSPGETATLSCRASQNVKNN DFHYGWIRQSSAKGLEWIGSIHWRGRTTHYKTSFRSR LAWYQLKPGQAPRLLIFDASSRAGGIPDRFSG AILSIDTSNNRFSLTFSFVTAADTAVYYCARHKYHDI SGYGTDFTLIVNSVQSEDFGDYFCQQYEEWPR FRVVPVAGWFDPWGQGLLVTVSS TFGQGTKVDIK 163 425 EVHLEESGPGLVRPSETLSLICTASGGSIRGGEWGDS 426 EIMMTQSPAILSVSPGDRATLSCRASQSVKNN DYHWGWVRHSPEKGLEWIGSIHWRGITHYNAPFRGRG LAWYQKRPGQAPRLLIFDTSSRASGIPARFSG RLSIDLSRNQFSLRLTSVTAEDTAVYYCVKHKYHDIV GGSGTEFTLTVNSMQSEDFATYYCQQYEEWPR MVVPIAGWFDPWGQGLQVTVSS TFGQGTKVEIK 164 427 QPQLQESGPGLVEASETLSLTCTVSGDSTAACDYFWG 428 QSALTQPPSASGSPGQSITISCTGNINNFVSW WVRQPPGKGLEWIGSLSHCAGYYNSGWTYHNPSLKSR YQQHPGKAPKLVIYGVNKRPSGVPDRFSGSKS LTISLDTPKNQVFLKLNSVTAADTAIYYCARFGGDVL GNAASLTVSGLQTDDEAVYYCGSLAGNWDVVF VYHDWPKPAWVDLWGRGVLVTVSS GGGTKLTVL 165 429 QPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWG 430 QSALTQPPSASGSPGQSITISCTGTSNNFVSW WVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSR YQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKS LTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVL GNTASLTVSGLQTDDEAVYYCGSLVGNWDVIF RYTDWPKPAWVDLWGRGTLVTVSS GGGTKLTVL 166 431 QPQLQESGPGLVEASETLSLTCTVSGDSTAGCDYFWG 432 QSALTQPPSASGSPGQSITISCTGTSNNFVSW WVRQPPGKGLEWIGGLSHCAGYYNTGWTYHNPSLKSR YQQHPAKAPKLVIYGVNKRPSGVPDRFSGSKS LTISLDTPKNQVFLKLNSVTAADTAIYYCARFDGEVL GNTASLTVSGLQTDDEAVYYCGSLVGNWDVIF VYNDWPKPAWVDLWGRGTLVTVSS GGGTKLTVL 167 433 QVQLQESGPGLVKPAETLSLTCSVSGESINTGHYYWG 434 QSALTQPPSASGSLGQSVTISCNGTSSDIGGW WVRQVPGKGLEWIGHIHYTTAVLHNPSLKSRLTIKIY NFVSWYQQFPGRAPRLIIFEVNKRPSGVPGRF TLRNQITLRLSNVTAADTAVYHCVRSGGDILYYYEWQ SGSKSGNSASLTVSGLQSDDEGQYFCSSLFGR KPHWFSPWGPGIHVTVSS WDVVFGGGTKLTVL 168 435 QVQLRESGPGLVKPSETLSLSCTVSQDSRPSDHSWTW 436 WASSELTQPPSVSVSPGQTARITCSGAPLTSR VRQSPGKALEWIGDIHYNGATTYNPSLRSRVRIELDQ FTYWYRQKPGQAPVLIISRSSQRSSGWSGRFS SIPRFSLKMTSMTAADTGMYYCARNAIRIYGVVALGE ASWSGTTVTLTIRGVQADDEADYYCQSSDTSD WFHYGMDVWGQGTAVTVSS SYKMFGGGTKLTVL 169 437 QVQLRESGPGLVKPSETLSLSCTVSNDSRPSDHSWTW 438 SSELTQPPSVSVSPGQTARITCSGAPLTSRFT VRQSPGKALEWIGDIHYNGATTYNPSLRSRVRIELDQ YWYRQKPGQAPVLIISRSSQRSSGWSGRFSAS SIPRFSLKMTSMTAADTGMYYCARNAIRIYGVVALGE WSGTTVTLTIRGVQADDEADYYCQSSDTSDSY WFHYGMDVWGQGTAVTVSS KMFGGGTKLTVL 170 439 EVQLRESGPRLVKPSETLSLSCDVFGDSRPSDHSWTW 440 SSELTQAPSVSVSPGQTATIACSGPPLASRYT VRQPPGKALEWIGDVHYNGDNTYNPSLRGRVKIDVDR YWYRQKPGQAPVLIIFRDRQFPSGVSGRFSAS STHRFSLTLKSLTAADTGIYFCARNVIRVFGVISLGE KSGTTATLTIRDVQVEDEGDYYCQSSDTSDSY WFHYGMDVWGPGTAVIVSS KMFGGGTTLTVL 171 441 EVQLRESGPGLVKPSETLSLSCDVFGDSRPSDHSWTW 442 SSELTQAPSVSVSPGQTATIACSGPPLASRYT VRQPPGKALEWIGDVHYNGDTTYNPSLRGRVKIDVDR YWYRQKPGQAPVLIIFRDRQFPSGVSGRFSAS STHRFSLTLNSLTAADTGIYFCARNVIRVFGVISLGE KSGTTATLTIRDVQVEDEGDYYCQSSDTSDSY WFHYGMDVWGQGTAVTVSS KMFGGGTTLTVL 172 443 QVQLRESGPGLVKPSETLSLICTVSNDSRPSDHSWTW 444 SSELTQPPSVSVSPGQTAKITCSGAALTSRFT VRQSPGKALEWIGDIHYNGATTYNPSLRSRVRIELDQ YWYRQKPGQAPVLIISRTSQRSSGWSGRFSAS SIPRFSLKMTSMTAADTGMYYCARNAIRIYGVVALGE WSGTTVTLTIRGVQADDEGDYYCQSSDTSDSY WFHYGMDVWGQGTAVTVSS KMFGGGTKLTVL 173 445 EVQLRESGPGLVKPSGNMALTCTISGDSRPSDHSWTW 446 SSELTQTPSVTVSPGETARIACSGPPLASRYC VRQSPGKALEWIGDIHYGGDITYNPSLRSRVKLEVDT YWYRQKPGQAPVLIIFRDRQFSSGMSGRFASS STNRFFLKMTSLTVADTGIYFCARNVIRVFGVIALGE HSGTTVTLTIRDVRVEDEADYYCQSSDINDSY WFHYGMDVWGQGTAITVSP KMFGGGTKVTVL 174 447 EVQLRESGPGLVKPSGNMALTCTISGDSRPSDHSWTW 448 SSELTQTASVTVSPGETARIACSGPPLASRYC VRQSPGKTLEWIGDIHYGGDITYNPSLRSRVKLEVDT YWYRQKPGQAPVLIIFRDRQFSSGISGRFSSS SSNRFFLKMTSLTVADTGIYFCARNVIRVFGVIALGE QSGTTVTLTIRDVRVEDEADYYCQSSDTSDSF WFHYGMDVWGQGTAITVSP KMFGGGTKLTVL 175 449 QVQLRESGPGLVKPSGNMALTCTISGDSRPSDHSWTW 450 SSELTQAPSVTVSPGDTARIACSGPPLATRYC VRQSPGKALEWIGDIHYGGDITYNPSLRSRVELEVDR YWYRQKSGQAPVLIIFRDRQFSSGVSGRFSSS STNRFFLKMTSLSVADTGMYFCARNVIRVFGVIALGE QSGSTVTLTIRDVRVEDEADYYCQSSDTSDSY WFHYGMDVWGQGTAITVSP KMFGGGTKLTVL 176 451 QVQLRESGPGLVKPSETLSLSCDVFGDSRPSDHSWTW 452 SSELTQAPSVSVSPGQTARIACSGPPLASRYT VRQPPGKALEWIGDIHYNGDKTYNPSLRGRVKIDVDR YWYRQKPGQAPVLIIFRDRQFPSGVSGRFSAS STHRFSLTLNSLTAADTGMYFCARNVIRVFGVISLGE KSGTTGILTIRDVQAEDEGDYYCQSSDTSDSY WFHYGMDVWGPGTAVTV KMFGGGTTLTVL 177 453 QVQLRESGPGLVKPSGNMALTCTISGDSRPSDHSWTW 454 SSELTQAPSVTLSPGETARIACSGPPLASRYC VRQSPGKALEWIGDIHYGGDITYNPSLRSRVKLEVDT YWYRQKPGQAPVLIIFRDRQFSSGISGRFSSS SSNRFFLKMTSLTVADTGIYFCARNVIRVFGVIALGE QSGTTVTLTIRDVRVEDEADYYCQSSDNSDSF WFHYGMDVWGQGTAITVSP KMFGGGTKLTVL 178 455 AEQLVESGGGLVPPGRSLRLSCSASGFYFPDYAMAWV 456 DIHMTQSPVSLSASVGDRVTITCRASHFIANY RQAPGQGLQWVGFMRGWAYGGSAQFAAFAVGKFAISR VNWYQQKPGKAPTLLIFESSTLQRGVPSRFSA DDGRNVVYLDVKNPTFEDTGVYFCAREQRNKDYRYGQ YGDGTEFTLSINTLQPEDFASYICQQSHSPPV EGFGYSYGMDVWGRGTTVVVST TFGAGTRVDQK 179 457 EERLVESGGGLVPPGRSLRLSCSAFDFYFPDYAMAWV 458 DILMTQSPVSLSASIGERITITCRASHFIANY RQAPGKGLEWIGFIRGWAYGQAAQYGKSASGRMTISR VNWYQQRPGKAPKLLIFQSWTLNRGIPSRFSG DDSRRVVYLDIKSPIEEDTGAYFCAREQRGGDGRYSG YGDGTEFTLSISALQSEDFGTYICQQSHSPPL DGFGYPYGMDVWGRGTMVTVSA SFGGGTRVDQT 180 459 EERLVESGGGLVPPGRSLRLSCSAFDFYFPDYAMAWV 460 DIQMTQSPFTLSASVGERVTITCRASHFIANY RQAPGRALEWIGFIRGWAYGQSAQYGKSASGRMTISR VNWYQQRPGRAPKLLIFESSTLNRGVPSRFSG DDSRRVVYLDIKSPTHEDTGVYFCAREQRGANGRYGG SGDGTEFTLSISALQSEDFATYICQQSHSPPV DGFGYSYGMDVWGRGTMVSVSA SFGGGTRVDQT

    [0123] In some embodiments, the anti-HIV gp120 V3 glycan-directed antibody or antigen-binding fragment thereof comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3; and a VL comprising a VL-CDR1, a VL-CDR2, and a second VH-CDR3; wherein the VH-CDR1, the VH-CDR2, the VH-CDR3 the VL-CDR1, the VL-CDR2, and the VH-CDR3 comprise the sequences set forth in: SEQ ID NOs.: 7, 8, 9, 10, 11 and 12; SEQ ID NOs.: 7, 13, 9, 10, 11 and 12; SEQ ID NOs.: 14, 15, 16, 17, 11 and 18; SEQ ID NOs.: 14, 19, 20, 17, 11 and 18; SEQ ID NOs.: 21, 22, 23, 24, 25 and 26; SEQ ID NOs.: 21, 22, 27, 24, 25 and 26; SEQ ID NOs.: 28, 29, 30, 31, 32 and 33; SEQ ID NOs.: 34, 35, 36, 37, 25 and 38; SEQ ID NOs.: 39, 40, 41, 42, 43 and 44; SEQ ID NOs.: 45, 46, 47, 48, 49 and 50; SEQ ID NOs.: 45, 51, 52, 53, 49 and 54; SEQ ID NOs.: 55, 56, 57, 58, 59 and 44; SEQ ID NOs.: 61, 46, 63, 58, 49 and 44; SEQ ID NOs.: 64, 65, 66, 67, 68 and 69; SEQ ID NOs.: 70, 71, 72, 73, 74 and 75; SEQ ID NOs.: 76, 77, 78, 79, 80 and 75; SEQ ID NOs.: 81, 82, 83, 84, 85 and 75; SEQ ID NOs.: 85, 86, 87, 88, 89 and 90; SEQ ID NOs.: 85, 91, 92, 93, 94 and 90; SEQ ID NOs.: 85, 96, 92, 93, 94 and 90; SEQ ID NOs.: 85, 86, 87, 97, 98 and 90; SEQ ID NOs.: 85, 99, 100, 101, 102 and 95; SEQ ID NOs.: 85, 99, 100, 101, 102 and 103; SEQ ID NOs.: 85, 99, 100, 104, 102 and 90; SEQ ID NOs.: 85, 105, 92, 93, 94 and 90; SEQ ID NOs.: 85, 99, 100, 101, 102 and 107; SEQ ID NOs.: 108, 109, 110, 111, 112, 113; SEQ ID NOs.: 108, 114, 115, 111, 116 and 117; or SEQ ID NOs.: 108, 118, 119, 111, 120 and 121 (CDRs according to Kabat).

    [0124] In some embodiments, the anti-HIV gp120 V3 glycan-directed antibody or antigen-binding fragment thereof comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3; and a VL comprising a VL-CDR1, a VL-CDR2, and a second VH-CDR3; wherein the VH-CDR1, the VH-CDR2, the VH-CDR3 the VL-CDR1, the VL-CDR2, and the VH-CDR3 comprise the sequences set forth in: SEQ ID NOs.: 123, 124, 9, 10, 11 and 12; SEQ ID NOs.: 125, 126, 16, 17, 11 and 18; SEQ ID NOs.: 127, 128, 20, 17, 11 and 18; SEQ ID NOs.: 129, 130, 23, 24, 25 and 26; SEQ ID NOs.: 129, 130, 27, 24, 25 and 26; SEQ ID NOs.: 131, 132, 30, 31, 32 and 33; SEQ ID NOs.: 133, 134, 36, 37, 25 and 38; SEQ ID NOs.: 135, 136, 41, 42, 43 and 44; SEQ ID NOs.: 137, 138, 47, 48, 49 and 50; SEQ ID NOs.: 137, 138, 52, 53, 49 and 54; SEQ ID NOs.: 139, 56, 57, 58, 59 and 44; SEQ ID NOs.: 141, 138, 63, 58, 49 and 44; SEQ ID NOs.: 142, 143, 66, 67, 68 and 69; SEQ ID NOs.: 144, 145, 72, 73, 74 and 75; SEQ ID NOs.: 146, 147, 78, 79, 80 and 75; SEQ ID NOs.: 146, 147, 83, 84, 85 and 75; SEQ ID NOs.: 149, 150, 87, 88, 89 and 90; SEQ ID NOs.: 151, 150, 87, 88, 89 and 90; SEQ ID NOs.: 152, 153, 92, 93, 94 and 90; SEQ ID NOs.: 151, 150, 87, 97, 98 and 90; SEQ ID NOs.: 152, 153, 100, 101, 102 and 95; SEQ ID NOs.: 152, 153, 100, 101, 102 and 103; SEQ ID NOs.: 152, 153, 100, 104, 102 and 90; SEQ ID NOs.: 152, 153, 100, 101, 102 and 107; SEQ ID NOs.: 154, 155, 110, 111, 116 and 117; SEQ ID NOs.: 156, 157, 115, 111, 116 and 117; or SEQ ID NOs.: 158, 159, 119, 111, 120 and 121 (CDRs according to Chothia).

    [0125] In some embodiments, the anti-HIV gp120 V3 glycan-directed antibody or antigen-binding fragment thereof comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3; and a VL comprising a VL-CDR1, a VL-CDR2, and a second VH-CDR3; wherein the VH-CDR1, the VH-CDR2, the VH-CDR3 the VL-CDR1, the VL-CDR2, and the VH-CDR3 comprise the sequences set forth in: SEQ ID NOs.: 160, 161, 162, 163, 164 and 12; SEQ ID NOs.: 165, 166, 167, 168, 164 and 18; SEQ ID NOs.: 165, 166, 461, 168, 164 and 18; SEQ ID NOs.: 169, 170, 171, 168, 164 and 18; SEQ ID NOs.: 172, 173, 174, 175, 164 and 26; SEQ ID NOs.: 172, 173, 176, 175, 164 and 26; SEQ ID NOs.: 177, 178, 179, 180, 164 and 38; SEQ ID NOs.: 181, 182, 183, 184, 185 and 33; SEQ ID NOs.: 186, 187, 188, 189, 190 and 44; SEQ ID NOs.: 191, 192, 193, 194, 195 and 50; SEQ ID NOs.: 191, 196, 197, 198, 195 and 54; SEQ ID NOs.: 199, 200, 201, 202, 399 and 44; SEQ ID NOs.: 203, 204, 205, 202, 195 and 44; SEQ ID NOs.: 206, 207, 208, 209, 210 and 69; 211, 212, 213, 214, 215 and 75; SEQ ID NOs.: 216, 217, 218, 219, 220 and 75; SEQ ID NOs.: 221, 217, 83, 223, 224 and 75; SEQ ID NOs.: 225, 226, 87, 227, 228 and 90; SEQ ID NOs.: 229, 226, 87, 227, 228 and 90; SEQ ID NOs.: 230, 231, 92, 232, 233 and 90; SEQ ID NOs.: 230, 234, 92, 232, 233 and 90; SEQ ID NOs.: 229, 226, 87, 235, 398 and 90; SEQ ID NOs.: 230, 236, 100, 232, 233 and 95; SEQ ID NOs.: 230, 236, 100, 232, 233 and 103; SEQ ID NOs.: 230, 236, 100, 237, 233 and 90; SEQ ID NOs.: 230, 238, 92, 232, 233 and 107; SEQ ID NOs.: 239, 240, 110, 241, 242 and 113; SEQ ID NOs.: 243, 244, 115, 241, 245 and 117; or SEQ ID NOs.: 243, 246, 119, 241, 247 and 121 (CDRs according to IMGT).

    [0126] In some embodiments, the anti-HIV gp120 V3 glycan-directed antibody or antigen-binding fragment thereof comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3; and a VL comprising a VL-CDR1, a VL-CDR2, and a second VH-CDR3; wherein the VH-CDR1, the VH-CDR2, the VH-CDR3 the VL-CDR1, the VL-CDR2, and the VH-CDR3 comprise the sequences set forth in: SEQ ID NOs.: 248, 249, 250, 251, 252 and 253; SEQ ID NOs.: 248, 254, 250, 251 252 and 253; SEQ ID NOs.: 255, 256, 257, 258, 252 and 259; SEQ ID NOs.: 260, 261, 262, 258, 252 and 259; SEQ ID NOs.: 263, 264, 265, 266, 267 and 268; SEQ ID NOs.: 263, 264, 397, 266, 267 and 268; SEQ ID NOs.: 269, 270, 271, 272, 273 and 274; SEQ ID NOs.: 275, 276, 277, 278, 279 and 280; SEQ ID NOs.: 281, 282, 283, 284, 285 and 286; SEQ ID NOs.: 287, 288, 289, 290, 291 and 286; SEQ ID NOs.: 287, 292, 293, 294, 295 and 296; SEQ ID NOs.: 297, 298, 299, 300, 301 and 286; SEQ ID NOs.: 302, 288, 303, 300, 295 and 286; SEQ ID NOs.: 304, 305, 306, 307, 308 and 309; SEQ ID NOs.: 310, 311, 312, 313, 314 and 315; SEQ ID NOs.: 316, 316, 318, 319, 320 and 315; SEQ ID NOs.: 321, 322, 323, 324, 325 and 315; 326, 327, 328, 329, 330 and 331; SEQ ID NOs.: 332, 327, 328, 329, 330 and 331; SEQ ID NOs.: 333, 334, 335, 336, 337 and 338; SEQ ID NOs.: 333, 339, 335, 336, 337 and 338; SEQ ID NOs.: 332, 327, 328, 340, 341 and 338; SEQ ID NOs.: 342, 343, 344, 336, 345 and 346; SEQ ID NOs.: 342, 343, 344, 336, 347 and 348; SEQ ID NOs.: 342, 343, 344, 349, 350 and 338; SEQ ID NOs.: 333, 351, 335, 336, 337 and 338; SEQ ID NOs.: 342, 343, 344, 336, 347 and 352; SEQ ID NOs: 353, 354, 355, 356, 357 and 358; SEQ ID NOs: 359, 360, 361, 356, 362 and 363; or SEQ ID NOs: 359, 364, 365, 356, 366 and 358. (CDRs according to Honegger).

    [0127] Illustrative embodiments of CDR sequences of an anti-HIV gp120 V3 glycan-directed antibody or antigen-binding fragment thereof, useful in the methods described herein, are provided in Tables A1-A4.

    [0128] In some embodiments, the anti-HIV gp120 V3 glycan-directed antibody or antigen-binding fragment thereof comprises VH and VL comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%, identical to the amino acid sequences set forth, respectively, as selected from: SEQ ID NOs.: 400 and 401; SEQ ID NOs.: 402 and 403; SEQ ID NOs.: 402 and 404; SEQ ID NOs.: 462 and 463; SEQ ID NOs.: 464 and 465; SEQ ID NOs.: 405 and 406; SEQ ID NOs.: 466 and 467; SEQ ID NOs.: 407 and 408; SEQ ID NOs.: 409 and 410; SEQ ID NOs.: 411 and 412; SEQ ID NOs.: 413 and 414; SEQ ID NOs.: 415 and 416; SEQ ID NOs.: 417 and 418; SEQ ID NOs.: 419 and 420; SEQ ID NOs.: 421 and 422; SEQ ID NOs.: 423 and 424; SEQ ID NOs.: 425 and 426; SEQ ID NOs.: 427 and 428; SEQ ID NOs.: 429 and 430; SEQ ID NOs.: 431 and 432; SEQ ID NOs.: 433 and 434; SEQ ID NOs.: 435 and 436; SEQ ID NOs.: 437 and 438; SEQ ID NOs.: 439 and 440; SEQ ID NOs.: 441 and 442; SEQ ID NOs.: 443 and 444; SEQ ID NOs.: 445 and 446; SEQ ID NOs.: 447 and 448; SEQ ID NOs.: 449 and 450; SEQ ID NOs.: 451 and 452; SEQ ID NOs.: 453 and 454; SEQ ID NOs.: 455 and 456; SEQ ID NOs.: 457 and 458; or SEQ ID NOs.: 459 and 460. Illustrative embodiments of variable domain VH and VL sequences of an anti-HIV gp120 V3 glycan-directed antibody or antigen-binding fragment thereof, useful in the methods described herein, are provided in Table B.

    [0129] In some embodiments, the anti-HIV gp120 V3 glycan directed antibody comprises VH and VL amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequences set forth below, respectively, and comprising one or more of the following amino acids at the indicated positions (position numbering according to Kabat): SEQ ID NOs.: 400 or 402, comprising one or more of: Ser-Ser-Val (SSV) or Thr-Gly-Val (TGV) at positions 82a-82c, Gln (Q) at position 39, Asn (N) at position 60, His (H) at position 68, any one of Lys (K), His (H) or Thr (T) at position 105, Leu (L) at position 2, Ala (A) at position 32, and/or Ala (A) at position 95; and SEQ ID NOs.: 401, 403 or 404 comprising one or more of: Gly (G) at position 67, Tyr (Y), Phe (F) or Thr (T) at position 67a, Arg (R) at position 67b, Pro (P) at position 67c, and/or Lys (K) at position 103. In some embodiments, the anti-HIV gp120 V3 glycan directed antibody comprises VH and VL amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequences set forth below, respectively, and comprising one or more of the following amino acids at the indicated positions (position numbering according to Kabat): SEQ ID NO.: 400 or 402, comprising one or more of: Thr-Gly-Val (TGV) at positions 82a-82c, Asn (N) at position 60, His (H) at position 68, any one of Lys (K), His (H) and/or Thr (T) at position 105; and SEQ ID NOs.: 401, 403 or 404 comprising one or more of: Gly (G) at position 67, Tyr (Y), Phe (F) or Thr (T) at position 67a, Arg (R) at position 67b, Pro (P) at position 67c.

    Fc Mutations that Increase Serum Half-Life

    [0130] In some embodiments, the Fc region or Fc domain of the anti-HIV gp120 V3 glycan directed antibody comprise amino acid modifications that promote an increased serum half-life of the anti-binding molecule. Mutations that increase the half-life of an antibody have been described. In one embodiment, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain comprise a methionine to tyrosine substitution at position 252 (EU numbering), a serine to threonine substitution at position 254 (EU numbering), and a threonine to glutamic acid substitution at position 256 (EU numbering). See, e.g., U.S. Pat. No. 7,658,921. This type of mutant, designated as a YTE mutant exhibits a four-fold increased half-life relative to wild-type versions of the same antibody (Dall'Acqua, et al., J Biol Chem, 281: 23514-24 (2006); Robbie, et al., Antimicrob Agents Chemotherap., 57(12):6147-6153 (2013)). In certain embodiments, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain comprise an IgG constant domain comprising one, two, three or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436 (EU numbering). Alternatively, M428L and N434S (LS) substitutions can increase the pharmacokinetic half-life of the multi-specific antigen binding molecule. In other embodiments, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain comprise a M428L and N434S substitution (EU numbering). In other embodiments, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain comprise T250Q and M428L (EU numbering) mutations. In other embodiments, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain comprise H433K and N434F (EU numbering) mutations.

    Fc Mutations that Enhance Effector Activity

    [0131] In some embodiments, the Fc region or Fc domain of the anti-HIV gp120 V3 glycan directed antibody comprise post-translational and/or amino acid modifications that increase effector activity, e.g., have improved FcIIIa binding and increased antibody-dependent cellular cytotoxicity (ADCC). In some embodiments, the Fc region or Fc domain of the anti-HIV gp120 V3 glycan directed antibody comprises DE modifications (i.e., S239D and I332E by EU numbering) in the Fc region. In some embodiments, the Fc region or Fc domain of the anti-HIV gp120 V3 glycan directed antibody comprises DEL modifications (i.e., S239D, I332E and A330L by EU numbering) in the Fc region. In some embodiments, the Fc region or Fc domain of the anti-HIV gp120 V3 glycan directed antibody comprises DEA modifications (i.e., S239D, I332E and G236A by EU numbering) in the Fc region. In some embodiments, the Fc region or Fc domain of the anti-HIV gp120 V3 glycan directed antibody comprises DEAL modifications (i.e., S239D, I332E, G236A and A330L by EU numbering) in the Fc region. See, e.g., U.S. Pat. Nos. 7,317,091; 7,662,925; 8,039,592; 8,093,357; 8,093,359; 8,383,109; 8,388,955; 8,735,545; 8,858,937; 8,937,158; 9,040,041; 9,353,187; 10,184,000; and 10,584,176. Additional amino acid modifications that increase effector activity, e.g., have improved FcIIIa binding and increased antibody-dependent cellular cytotoxicity (ADCC) include without limitation (EU numbering) F243L/R292P/Y300L/V305I/P396L; S298A/E333A/K334A; or L234Y/L235Q/G236W/S239M/H268D/D270E/S298A on a first Fc domain and D270E/K326D/A330M/K334E on a second Fc domain. Amino acid mutations that increase C1q binding and complement-dependent cytotoxicity (CDC) include without limitation (EU numbering) S267E/H268F/S324T or K326W/E333S. Fc region mutations that enhance effector activity are reviewed in, e.g., Wang, et al., Protein Cell (2018) 9(1): 63-73; and Saunders, Front Immunol. (2019) 10:1296.

    [0132] In other embodiments, the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment thereof has modified glycosylation, which, e.g., may be introduced post-translationally or through genetic engineering. In some embodiments, the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment thereof is afucosylated, e.g., at a glycosylation site present in the antibody or antigen-binding fragment thereof. Most approved monoclonal antibodies are of the IgG1 isotype, where two N-linked biantennary complex-type oligosaccharides are bound to the Fc region. The Fc region exercises the effector function of ADCC through its interaction with leukocyte receptors of the FcR family. Afucosylated monoclonal antibodies are monoclonal antibodies engineered so that the oligosaccharides in the Fc region of the antibody do not have any fucose sugar units.

    [0133] In some embodiments, as appropriate, the Fc region or Fc domain of the anti-HIV gp120 V3 glycan directed antibody can comprise post-translational and/or amino acid modifications for increasing serum half-life and enhancing effector activity.

    [0134] 4. Combination Therapies with Two or More Anti-HIV Antibodies

    [0135] In certain embodiments, this disclosure provides a method for treating or preventing an HIV infection in a human subject having, or at risk of having, the HIV infection. The method comprises administering to the human subject a therapeutically effective amount of an anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment, as disclosed herein, or a pharmaceutical composition thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method for treating an HIV infection in a human subject having or at risk of having the infection is provided, the method comprising administering to the human subject a therapeutically effective amount of an antibody or antibodies disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

    Antibody Combination Therapy

    [0136] In some embodiments, the anti-V3-glycan antibody or antigen-binding fragment thereof is co-administered with a second anti-HIV antibody. In some embodiments, the anti-V3-glycan antibody or antigen-binding fragment thereof is co-administered with a second anti-HIV antibody that binds to an epitope or region of gp120 selected from the group consisting of: (i) second variable loop (V2) and/or Env trimer apex; (ii) CD4 binding site (CD4bs); (iii) gp120/gp41 interface; or (v) silent face of gp120. The foregoing epitopes or regions of gp120 bound by broadly neutralizing antibodies are described, e.g., in McCoy, Retrovirology (2018) 15:70; Sok and Burton, Nat Immunol. 2018 19(11):1179-1188; Possas, et al., Expert Opin Ther Pat. 2018 July; 28(7):551-560; and Stephenson and Barouch, Curr HIV/AIDS Rep (2016) 13:31-37, which are hereby incorporated herein by reference in their entirety for all purposes.

    [0137] In some embodiments, the combination therapy entails co-administration of an anti-V3-glycan antibody or antigen-binding fragment thereof and another anti-HIV broadly neutralizing antibody or bNAb (i.e., a neutralizing antibody that neutralizes multiple HIV-1 viral strains). Various bNAbs are known in the art and may be used as a combining therapeutic agent. Additional illustrative bNAbs of use include, those that comprise VH and VL that bind to or compete with an epitope or region of gp120 selected from the group consisting of: (i) second variable loop (V2) and/or Env trimer apex; (ii) CD4 binding site (CD4bs); (iii) gp120/gp41 interface; or (v) silent face of gp120. Illustrative bNAbs for use in anti-HIV antibody combination therapies include those that comprise VH and VL that bind to or compete with 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, and LN01 (all of which bind the MPER of gp41); PG9, PG16, CH01-04 (all of which bind V1V2-glycan), 2G12 (which binds to outer domain glycan); b12, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 VRC08, VRC0801, NIH45-46, GS-9723, GS-5423, 3BNC117, 3BNC60, VRC-PG04, PGV04; CH103, 44-VRC13.01, 1NC9, 12A12, N6, N6LS (VRC-HIVMAB091-00-AB), N49-P7, NC-Cow1, IOMA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9 and N60P25 (all of which bind to the CD4 binding site).

    [0138] In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of gp120 in the second variable loop (V2) and/or Env trimer apex and competes with or comprises CDRs and/or VH and VL regions from an antibody selected from the group consisting of PG9, PG16, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CH01, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01.

    [0139] In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of gp120 in the CD4 binding site (CD4bs) and competes with or comprises CDRs and/or VH and VL regions from an antibody selected from the group consisting of b12, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 VRC08, VRC0801, NIH45-46, GS-9723, GS-5423, 3BNC117, 3BNC60, VRC-PG04, PGV04; CH103, 44-VRC13.01, 1NC9, 12A12, N6, N6LS (VRC-HIVMAB091-00-AB), N49-P7, NC-Cow1, IOMA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9 and N60P25.

    [0140] In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of gp120 in the gp120/gp41 interface and competes with or comprises CDRs and/or VH and VL regions from an antibody selected from the group consisting of PGT-151, CAP248-2B, 35O22, 8ANC195, ACS202, VRC34 and VRC34.01.

    [0141] In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of the gp120 silent face and competes with or comprises second VH and VL regions from antibody VRC-PG05.

    [0142] In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of gp41 in the membrane proximal region (MPER) and competes with or comprises second VH and VL regions from an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01. In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of KLIC (KLIC disclosed as SEQ ID NO: 468), an immutable site of the transmembrane protein gp41 and competes with or comprises second VH and VL regions from Clone 3 human monoclonal antibody (C13hmAb) (Protheragen). See, e.g., Vanini, et al., AIDS. (1993) 7(2):167-74.

    [0143] In some embodiments, the combination therapy includes an antibody that binds to and epitope or region of the gp41 fusion peptide and competes with or comprises second VH and VL regions from an antibody selected from the group consisting of VRC34 and ACS202.

    [0144] In some embodiments, the combination therapy includes a multi-specific, e.g., a bispecific or tri-specific antibody that binds to an HIV antigen. Examples of HIV bispecific and trispecific antibodies include MGD014, B12BiTe, BiIA-SG, TMB-bispecific, SAR-441236, VRC-01/PGDM-1400/10E8v4, 10E8.4/iMab, and 10E8v4/PGT121-VRC01.

    [0145] Prior to administration, the bNAbs may be improved to have enhanced drug-like-properties, reduced immunogenicity, enhanced ADCC, and suitable pharmacokinetic properties. Such antibodies were shown to bind to the HIV envelope glycoprotein expressed on the surface of virion or infected cells, and mediate both direct neutralization of the virus as well as potent NK, Monocyte and PBMC killing of these cells. This property allows the antibodies to treat HIV infections by neutralizing the virus, and also kill and eliminate latently HIV infected cells in infected individuals, potentially leading to a sterilizing cure for HIV.

    [0146] In various embodiments, all antibodies administered in a combination anti-HIV antibody therapy can have Fc and/or post-translational modifications that increase serum half-life and/or enhance effector activity, as described above.

    [0147] In various embodiments, the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragments, and optionally combined bNAbs, can be in vivo delivered, e.g., expressed in vivo from administered mRNA or engineered B-cells. Examples of in vivo delivered bNAbs include AAV8-VRC07; mRNA encoding anti-HIV antibody VRC01; and engineered B-cells encoding 3BNC117 (Hartweger et al, J. Exp. Med. 2019, 1301).

    [0148] 5. Combination Therapies with Other Anti-HIV Therapeutic Agents

    [0149] In certain embodiments, a method for treating or preventing an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragments, as disclosed herein, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method for treating an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragments, as disclosed herein, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

    [0150] In one embodiment, pharmaceutical compositions comprising the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragments, as disclosed herein, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient are provided.

    [0151] In certain embodiments, provided are methods for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment thereof, as described herein, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.

    [0152] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment thereof is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment thereof is combined with two additional therapeutic agents. In other embodiments, the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment thereof is combined with three additional therapeutic agents. In further embodiments, the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment thereof is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, (e.g., one or more anti-HIV broadly neutralizing antibodies), and/or they can be selected from different classes of therapeutic agents.

    Administration of HIV Combination Therapy

    [0153] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment thereof, as described herein, is co-administered with one or more additional therapeutic agents. Co-administration of an anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of an anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments disclosed herein and the one or more additional therapeutic agents are both present in the body of the patient. When administered sequentially, the combination may be administered in two or more administrations.

    [0154] Co-administration includes concurrent administration as well as administration of unit dosages of the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment thereof, as described herein before or after administration of unit dosages of one or more additional therapeutic agents. For example, the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment thereof, as described herein, may be administered within seconds, minutes, hours or days of the administration of the one or more additional therapeutic agents. In some embodiments, a unit dose of an anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments disclosed herein is administered first, followed within seconds, minutes, hours or days by administration of a unit dose of one or more additional therapeutic agents. Alternatively, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of an anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments disclosed herein within seconds, minutes, hours or days. In other embodiments, a unit dose of an anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours, 1-24 hours, 1-36 hours, 1-48 hours, 1-60 hours, 1-72 hours), by administration of a unit dose of one or more additional therapeutic agents. In yet other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours, 1-24 hours, 1-36 hours, 1-48 hours, 1-60 hours, 1-72 hours), by administration of a unit dose of an anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments disclosed herein.

    [0155] In certain embodiments, an anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid, liquid or suspension dosage form for oral, intravenous, intramuscular or subcutaneous administration.

    [0156] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments are formulated as a liquid solution or suspension which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the liquid solution or suspension can contain another active ingredient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

    [0157] In certain embodiments, such liquid solutions or suspensions are suitable for once daily, once weekly (i.e., QW), once bi-weekly (i.e. once every other week, or once every two weeks or Q2W), once monthly (i.e., QM) or once bi-monthly dosing (i.e. once every other month, or once every two months or Q2M) dosing or administration intervals. In some embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments are administered once daily, once weekly (i.e., QW), once bi-weekly (i.e. once every other week, or once every two weeks or Q2W), once monthly (i.e., QM), once bi-monthly dosing (i.e. once every other month, or once every two months or Q2M), once every three months (i.e., Q3M), once every four months (i.e., Q4M),

    HIV Combination Therapy

    [0158] In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, HIV Tat or Rev inhibitors, immunomodulators, (e.g., immunostimulators), immunotherapeutic agents, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cell therapies (such as chimeric antigen receptor T-cell, CAR-T, and engineered T-cell receptors, TCR-T, autologous T-cell therapies), latency reversing agents, compounds that target the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and antibody-like therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, Fatty acid synthase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators (e.g., Nef inhibitors), Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-Glycoprotein modulators, TAT protein inhibitors, prolylendopeptidase inhibitors, Phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, TNF alpha ligand inhibitors, IFN antagonists, HIV vaccines, and combinations thereof.

    [0159] In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, HIV capsid inhibitors, HIV Tat or Rev inhibitors, immunomodulators, (e.g., immunostimulators), immunotherapeutic agents, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and antibody-like therapeutic proteins, and combinations thereof.

    HIV Combination Drugs

    [0160] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with one, two, three, four or more additional anti-HIV therapeutic agents. Example anti-HIV therapeutic agents that can be combined include without limitation ATRIPLA (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA (EVIPLERA; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY (tenofovir alafenamide and emtricitabine); ODEFSEY (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); BIKTARVY (bictegravir+emtricitabine+tenofovir alafenamide), adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir alafenamide and elvitegravir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; PEGylated raltegravir; raltegravir and lamivudine; maraviroc; tenofovir+emtricitabine+maraviroc, enfuvirtide; ALUVIA (KALETRA; lopinavir and ritonavir); COMBIVIR (zidovudine and lamivudine; AZT+3TC); EPZICOM (LIVEXA; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir+lamivudine, lamivudine+abacavir+zidovudine, lamivudine+abacavir, lamivudine+tenofovir disoproxil fumarate, lamivudine+zidovudine+nevirapine, lopinavir+ritonavir, lopinavir+ritonavir+abacavir+lamivudine, lopinavir+ritonavir+zidovudine+lamivudine, tenofovir+lamivudine, and tenofovir disoproxil fumarate+emtricitabine+rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine and lamivudine; cabotegravir+rilpivirine; elpida (elsulfavirine; VM-1500; VM-1500A); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; efavirenz, lamivudine, and emtricitabine; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

    Other HIV Drugs

    [0161] Examples of other drugs for treating HIV that can be combined with an agent of this disclosure include aspernigrin C, acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-sh1-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, bevirimat derivatives, ABX-464, AG-1105, APH-0812, bryostatin analogs, BIT-225, CYT-107, CS-TATI-1, fluoro-beta-D-arabinose nucleic acid (FANA)-modified antisense oligonucleotides, FX-101, griffithsin, HGTV-43, HPH-116, HS-10234, hydroxychloroquine, IMB-10035, IMO-3100, IND-02, JL-18008, LADAVRU, MK-1376, MK-2048, MK-4250, MK-8507, MK-8558, MK-8591 (islatravir), NOV-205, OB-002H, ODE-Bn-TFV, M1-TFV, PA-1050040 (PA-040), PC-707, PGN-007, QF-036, S-648414, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, DIACC-1010, Fasnall, Immuglo, 2-CLIPS peptide, HRF-4467, thrombospondin analogs, TBL-1004HI, VG-1177, x1-081, rfhSP-D, [.sup.18F]-MC-225, URMC-099-C, RES-529, and VIR-576.

    HIV Protease Inhibitors

    [0162] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an HIV protease inhibitor. Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, AEBL-2, DG-17, GS-1156, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, GRL-02031 and TMC-310911.

    HIV Ribonuclease H Inhibitors

    [0163] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an HIV ribonuclease H inhibitor. Examples of HIV ribonuclease H inhibitors that can be combined include NSC-727447.

    HIV Nef Inhibitors

    [0164] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an HIV Nef inhibitor. Examples of HIV Nef inhibitors that can be combined with include FP-1.

    HIV Reverse Transcriptase Inhibitors

    [0165] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a non-nucleoside or non-nucleotide inhibitor. Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, ACC-008, AIC-292, F-18, KM-023, PC-1005, VM-1500A-LAI, PF-3450074, elsulfavirine (sustained release oral, HIV infection), elsulfavirine (long-acting injectable nanosuspension, HIV infection), and elsulfavirine (VM-1500).

    [0166] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an HIV nucleoside or nucleotide inhibitor. Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester (AGX-1009), tenofovir disoproxil hemifumarate, VIDEX and VIDEX EC (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500 and KP-1461.

    HIV Integrase Inhibitors

    [0167] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an HIV integrase inhibitor. Examples of HIV integrase inhibitors include elvitegravir, elvitegravir (extended-release microcapsules), curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, PEGylated raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long-acting injectable), diketo quinolin-4-1 derivatives, integrase-LEDGF inhibitor, ledgins, M-522, M-532, MK-0536, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T-169, STP-0404, VM-3500 and cabotegravir.

    [0168] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a HIV non-catalytic site, or allosteric, integrase inhibitor (NCINI). Examples of HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) include CX-05045, CX-05168, and CX-14442.

    HIV Entry Inhibitors

    [0169] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an HIV entry inhibitor. Examples of HIV entry (fusion) inhibitors include AAR-501, LBT-5001, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, gp160 inhibitors and CXCR4 inhibitors.

    [0170] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a CCR5 inhibitor. Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, maraviroc (long-acting injectable nanoemulsion), cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, thioraviroc and vMIP (Haimipu).

    [0171] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a CXCR4 inhibitor. Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

    [0172] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a gp41 inhibitor. Examples of gp41 inhibitors include albuvirtide, enfuvirtide, griffithsin (gp41/gp120/gp160 inhibitor), BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, C13hmAb, PIE-12 trimer and sifuvirtide.

    [0173] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a CD4 attachment inhibitor. Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs

    [0174] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a gp120 inhibitor. Examples of gp120 inhibitors include anti-HIV microbicide, Radha-108 (receptol) 3B3-PE38, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, VVX-004, and BMS-663068.

    [0175] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a gp160 inhibitor. Examples of gp160 inhibitors that can be combined include fangchinoline.

    HIV Maturation Inhibitors

    [0176] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an HIV maturation inhibitor. Examples of HIV maturation inhibitors include BMS-955176, GSK-3640254 and GSK-2838232.

    Latency Reversing Agents

    [0177] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an HIV latency reversing agent. Examples of latency reversing agents that can be combined with the one or more multi-specific antigen binding molecules, described herein, include IL-15 receptor agonists (e.g., ALT-803; interleukin-15/Fc fusion protein (e.g., XmAb24306); recombinant interleukin-15 (e.g., AM0015, NIZ-985); pegylated IL-15 (e.g., NKTR-255)); toll-like receptor (TLR) agonists (including TLR7 agonists, e.g., GS-9620 and TLR8 agonists, e.g., GS-9688), histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, IAP antagonists (inhibitor of apoptosis proteins, such as APG-1387, LBW-242), SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406), Debio-1143, PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), NIZ-985, IL-15 modulating antibodies, (including IL-15, IL-15 fusion proteins and IL-15 receptor agonists, e.g., ALT-803), JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, APH-0812, and GSK-343. Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat. Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactones.

    Toll-Like Receptor (TLR) Agonists

    [0178] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an agonist of a toll-like receptor (TLR), e.g., an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and/or TLR10 (NCBI Gene ID: 81793). Example TLR7 agonists that can be co-administered or combined with the one or more multi-specific antigen binding molecules, described herein, include without limitation AL-034, DSP-0509, GS-9620 (vesatolimod), vesatolimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and the compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). An TLR7/TLR8 agonist that can be co-administered is NKTR-262, telratolimod and BDB-001. Example TLR8 agonists that can be co-administered or combined with the one or more multi-specific antigen binding molecules, described herein, include without limitation E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). Example TLR9 agonists that can be co-administered include without limitation AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod and PUL-042. Examples of TLR3 agonist include rintatolimod, poly-ICLC, RIBOXXON, Apoxxim, RIBOXXIM, IPH-33, MCT-465, MCT-475, and ND-1.1. Examples of TLR4 agonist include G-100, and GSK-1795091.

    Histone Deacetylase (HDAC) Inhibitors

    [0179] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an inhibitor of a histone deacetylase, e.g., histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include without limitation, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, romidepsin, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

    Cyclin-Dependent Kinase (CDK) Inhibitors or Antagonists

    [0180] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an inhibitor or antagonist of a cyclin-dependent kinase (CDK), e.g., cyclin dependent kinase 4 (CDK4; NCBI Gene ID: 1019), cyclin dependent kinase 6 (CDK6; NCBI Gene ID: 1021), cyclin dependent kinase 9 (CDK9; NCBI Gene ID: 1025). In some embodiments, the CDK4/CDK6/CDK9 inhibitor or antagonist is selected from the group consisting of VS2-370.

    Stimulator of Interferon Genes (STING) Agonists

    [0181] In some embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an stimulator of interferon genes (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic-GAMP (cGAMP) and cyclic-di-AMP.

    RIG-I Agonists

    [0182] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an agonist of DExD/H-box helicase 58 (DDX58; a.k.a., RIG-I, RIG1, RIGI, RLR-1, SGMRT2; NCBI Gene ID: 23586). In some embodiments, the agents described herein are combined with a RIG-I modulator such as RGT-100, or NOD2 modulator, such as SB-9200 (a.k.a., GS 9992; inarigivir), and IR-103. An illustrative RIG-I agonist is KIN1148, described by Hemann, et al., J Immunol May 1, 2016, 196 (1 Supplement) 76.1. Additional RIG-I agonists are described, e.g., in Elion, et al., Cancer Res. (2018) 78(21):6183-6195; and Liu, et al., J Virol. (2016) 90(20):9406-19. RIG-I agonists are commercially available, e.g., from Invivogen (invivogen.com).

    LAG-3 and TIM-3 Inhibitors

    [0183] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an anti-TIM-3 (a.k.a., hepatitis A virus cellular receptor 2 antibody (HAVCR2; NCBI Gene ID: 84868), such as TSR-022, LY-3321367, MBG-453, INCAGN-2390. In some embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an anti-LAG-3 (Lymphocyte-activation) (NCBI Gene ID: 3902) antibody, such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385.

    Capsid Inhibitors

    [0184] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a capsid inhibitor. Examples of capsid inhibitors that can be combined with an agent of this disclosure include capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, GS-6207, GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series, PF-3450074, and compounds described in Intl. Patent Publ. No. WO 2019/087016.

    Immune-Based Therapies

    [0185] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an immune-based therapy. Examples of immune-based therapies include toll-like receptor (TLR) modulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, AND TLR13; programmed cell death protein 1 (PD-1) modulators; programmed death-ligand 1 (PD-L1) modulators; IL-15 modulators (e.g., IL-15 receptor agonists (e.g., ALT-803; interleukin-15/Fc fusion protein (e.g., XmAb24306); recombinant interleukin-15 (e.g., AM0015, NIZ-985); pegylated IL-15 (e.g., NKTR-255)); DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; polymer polyethyleneimine (PEI); gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, normferon, peginterferon alfa-2a, peginterferon alfa-2b, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103.

    [0186] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a TLR agonist. Examples of TLR agonists include without limitation: vesatolimod (GS-9620), lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod.

    Immune Checkpoint Receptor Protein Modulators

    [0187] In various embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and/or with one or more stimulators, activators or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T-cell or NK cell activation and prevent immune escape of infected cells. Activation or stimulation of stimulatory immune check points can augment the effect of immune checkpoint inhibitors in infective therapeutics. In various embodiments, the immune checkpoint proteins or receptors regulate T cell responses (e.g., reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, the immune checkpoint proteins or receptors regulate NK cell responses (e.g., reviewed in Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688).

    [0188] Examples of immune checkpoint proteins or receptors that can be combined with the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein include without limitation CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell co-stimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activating 3 (CD223); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

    [0189] In various embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. Illustrative T-cell inhibitory immune checkpoint proteins or receptors include without limitation CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with one or more agonist or activators of one or more T-cell stimulatory immune checkpoint proteins or receptors. Illustrative T-cell stimulatory immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

    [0190] In various embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors. Illustrative NK-cell inhibitory immune checkpoint proteins or receptors include without limitation killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin like receptor D1 (KLRD1, CD94). In various embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with one or more agonist or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors. Illustrative NK-cell stimulatory immune checkpoint proteins or receptors include without limitation CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

    [0191] In some embodiments, the one or more immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprises a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4.

    [0192] Examples of inhibitors of CTLA4 that can be co-administered include without limitation ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4), and AK-104 (CTLA4/PD-1).

    [0193] Examples of inhibitors of PD-L1 (CD274) or PD-1 (PDCD1) that can be co-administered include without limitation pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181 (budigalimab), PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD-013 (PD-1/LAG-3), FS-118 (LAG-3/PD-L1) MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), RO-7121661 (PD-1/TIM-3), XmAb-20717 (PD-1/CTLA4), AK-104 (CTLA4/PD-1), M7824 (PD-L1/TGF-EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM3/PDL1), and INBRX-105 (4-1BB/PDL1).

    [0194] In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550 and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.

    [0195] In various embodiments, the antibodies or antigen-binding fragments as described herein are combined with anti-TIGIT antibodies, such as BMS-986207, RG-6058, AGEN-1307

    TNF Receptor Superfamily (TNFRSF) Member Agonists or Activators

    [0196] In various embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an agonist of one or more TNF receptor superfamily (TNFRSF) members, e.g., an agonist of one or more of TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNFRSF7 (CD27, NCBI Gene ID: 939), TNFRSF8 (CD30, NCBI Gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI Gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI Gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI Gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI Gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI Gene ID: 8792), TNFRSF11B (NCBI Gene ID: 4982), TNFRSF12A (CD266, NCBI Gene ID: 51330), TNFRSF13B (CD267, NCBI Gene ID: 23495), TNFRSF13C (CD268, NCBI Gene ID: 115650), TNFRSF16 (NGFR, CD271, NCBI Gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBI Gene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).

    [0197] Example anti-TNFRSF4 (OX40) antibodies that can be co-administered include without limitation, MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

    [0198] Example anti-TNFRSF5 (CD40) antibodies that can be co-administered include without limitation RG7876, SEA-CD40, APX-005M and ABBV-428.

    [0199] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

    [0200] Example anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include without limitation urelumab, utomilumab (PF-05082566), AGEN2373 and ADG-106.

    [0201] Example anti-TNFRSF18 (GITR) antibodies that can be co-administered include without limitation, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, an antibody, or fragment thereof, co-targeting TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, e.g., in WO2017096179 and WO2018089628.

    Interleukin Receptor Agonists

    [0202] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an interleukin receptor agonist, such as IL-2, IL-7, IL-15, IL-10, IL-12 agonists; examples of IL-2 receptor agonists such as proleukin (aldesleukin, IL-2); pegylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bempegaldesleukin, AIC-284, ALKS-4230, CUI-101, Neo-2/15; IL-15 receptor agonists, such as ALT-803, NKTR-255, and hetIL-15, interleukin-15/Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 Synthorin (pegylated IL-15), P-22339, and a IL-15-PD-1 fusion protein N-809; examples of IL-7 include CYT-107.

    [0203] Examples of additional interleukin receptor agonists that can be combined with the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein include interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; Flt3 agonists such as CDX-301; gepon; normferon, peginterferon alfa-2a, peginterferon alfa-2b, RPI-MN.

    Bi- and Tri-Specific Natural Killer (NK)-Cell Engagers

    [0204] In various embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a bi-specific NK-cell engager (BiKE) or a tri-specific NK-cell engager (TriKE) (e.g., not having an Fc) or bi-specific antibody (e.g., having an Fc) against an NK cell activating receptor, e.g., CD16A, C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H and NKG2F), natural cytotoxicity receptors (NKp30, NKp44 and NKp46), killer cell C-type lectin-like receptor (NKp65, NKp80), Fc receptor FcR (which mediates antibody-dependent cell cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1 and CD137 (4-1BB). Illustrative anti-CD16 bi-specific antibodies, BiKEs or TriKEs that can be co-administered include AFM26 (BCMA/CD16A) and AFM-13 (CD16/CD30). As appropriate, the anti-CD16 binding bi-specific molecules may or may not have an Fc. BiKEs and TriKEs are described, e.g., in Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54. Examples of a trispecific NK cell engager (TRiKE) include OXS-3550, and CD16-IL-15-B7H3 TriKe.

    Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

    [0205] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a PI3K inhibitor. Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474.

    Alpha-4/Beta-7 Antagonists

    [0206] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an alpha-4/beta-7 antagonist. Examples of Integrin alpha-4/beta-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

    Pharmacokinetic Enhancers

    [0207] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a pharmacokinetic enhancer. Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

    Additional Therapeutic Agents

    [0208] Examples of additional therapeutic agents include the compounds disclosed in WO 2004/096286 (Gilead Sciences); WO 2006/015261 (Gilead Sciences); WO 2006/110157 (Gilead Sciences); WO 2012/003497 (Gilead Sciences); WO 2012/003498 (Gilead Sciences); WO 2012/145728 (Gilead Sciences); WO 2013/006738 (Gilead Sciences); WO 2013/159064 (Gilead Sciences); WO 2014/100323 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380 (Japan Tobacco); WO 2009/062285 (Boehringer Ingelheim); WO 2010/130034 (Boehringer Ingelheim); WO 2013/006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013/091096 (Boehringer Ingelheim).

    HIV Combination Therapy

    [0209] In a particular embodiment, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with one, two, three, four or more additional therapeutic agents selected from ATRIPLA (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA (EVIPLERA; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY (tenofovir alafenamide and emtricitabine); ODEFSEY (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA (KALETRA; lopinavir and ritonavir); COMBIVIR (zidovudine and lamivudine; AZT+3TC); EPZICOM (LIVEXA; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

    [0210] It will be appreciated by one of skill in the art that the additional therapeutic agents listed above may be included in more than one of the classes listed above. The particular classes are not intended to limit the functionality of those compounds listed in those classes.

    [0211] In a specific embodiment, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In an additional embodiment, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

    [0212] In a particular embodiment, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

    [0213] In a particular embodiment, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

    [0214] In a particular embodiment, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

    [0215] In a particular embodiment, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

    [0216] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with one or more additional therapeutic agents in a therapeutically effective dosage amount in the range of e.g., from 1 mg to 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 1000 mg or 1500 mg of the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment. In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with one or more additional therapeutic agents in a therapeutically effective dosage amount in the range of e.g., from about 0.1 mg/kg to about 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 8 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg or 50 mg/kg of the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment. In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with one or more additional therapeutic agents in a therapeutically effective dosage amount in the range of e.g., from about 5 mg to about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, 250 mg, 300 mg, 500 mg, 1000 mg or 1500 mg of the anti-HIV gp120 V3 glycan directed antibody or antigen-binding fragment.

    [0217] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In some embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with the agents provided herein in any dosage amount of the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments (e.g., from 1 mg to 500 mg of the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments, as described herein) the same as if each combination of dosages were specifically and individually listed.

    [0218] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine. The anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments may be combined with the agents provided herein in any dosage amount (e.g., from 1 mg to 500 mg of the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments) the same as if each combination of dosages were specifically and individually listed.

    Long-Acting HIV Inhibitors

    [0219] In some embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein can be co-administered with a long-acting HIV inhibitor. Examples of drugs that are being developed as long acting HIV inhibitors include without limitation: cabotegravir LA, rilpivirine LA, any integrase LA, VM-1500 LAI, maraviroc (LAI), tenofovir implant, MK-8591 implant, long-acting dolutegravir.

    [0220] In one embodiment, kits comprise the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

    HIV Vaccines

    [0221] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with an HIV vaccine. Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenoviral vector vaccines (e.g., Ad5, Ad26 or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenoviral vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), Coxsackieviruses based vaccines, enteric virus based vaccines, Gorilla adenovirus vaccines, lentiviral vector based vaccine, bi-segmented or tri-segmented arenavirus based vaccines (e.g., LCMV, Pichinde), trimer-based HIV-1 vaccine, measles virus based vaccine, flavivirus vector based vaccines, tobacco mosaic virus vector based vaccine, Varicella-zoster virus based vaccine, Human parainfluenza virus 3 (PIV3) based vaccines, poxvirus based vaccine (modified vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, and avipoxvirus-derived ALVAC (canarypox virus) strains); fowlpox virus based vaccine, rhabdovirus-based vaccines, such as Vesicular stomatitis virus (VSV) and marabavirus; recombinant human CMV (rhCMV) based vaccine, alphavirus-based vaccines, such as semliki forest virus, venezuelan equine encephalitis virus and sindbis virus (see, e.g., Lauer, et al., Clin Vaccine Immunol. (2017) 24(1): e00298-16); LNP formulated mRNA based therapeutic vaccines; and LNP-formulated self-replicating RNA/self-amplifying RNA vaccines.

    [0222] Examples of HIV vaccines include without limitation anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664 gp140 adjuvanted vaccine, BG505 SOSIP.GT1.1 gp140 adjuvanted vaccine, Chimigen HIV vaccine, ConM SOSIP.v7 gp140, rgp120 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, MPER-656 liposome subunit vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-05, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A/B/C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G/MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines, TatImmune, GTU-multiHIV (FIT-06), ChAdV63.HIVconsv, gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-EnvF, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, N123-VRC-34.01 inducing epitope-based HIV vaccine, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, GOVX-055, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, ENOB-HV-11, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, MagaVax, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, DNA and Sev vectors vaccine expressing SCaVII, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV+MVA mosaic vaccine+gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, VIR-1111, IHV-001, and virus-like particle vaccines such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B/C fusion vaccine, GTU-based DNA vaccine, HIV gag/pol/nef/env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptides vaccine, dendritic-cell vaccines, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), I i-key/MHC class II epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x+romidepsin, variant gp120 polypeptide vaccine, rAd5 gag-pol env A/B/C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP+VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer based vaccine, PD-201401, env (A, B, C, A/E)/gag (C) DNA Vaccine, gp120 (A, B, C, A/E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvanted), HIV p24gag prime-boost plasmid DNA vaccine, HIV-1 iglb12 neutralizing VRC-01 antibody-stimulating anti-CD4 vaccine, MVA-BN HIV-1 vaccine regimen, UBI HIV gp120, mRNA based prophylactic vaccines, VPI-211, and TBL-1203HI.

    Birth Control (Contraceptive) Combination Therapy

    [0223] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a birth control or contraceptive regimen. Therapeutic agents used for birth control (contraceptive) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl Estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norelgestromin, norethindrone, noretynodrel, norgestimate, ormeloxifene, segestersone acetate, ulipristal acetate, and any combinations thereof.

    Gene Therapy and Cell Therapy

    [0224] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a gene or cell therapy regimen. Gene therapy and cell therapy include without limitation the genetic modification to silence a gene; genetic approaches to directly kill the infected cells; the infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to infected cells, or activate the patient's own immune system to kill infected cells, or find and kill the infected cells; genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against the infection. Examples of cell therapy include LB-1903, ENOB-HV-01, GOVX-B01, and SupT1 cell based therapy. Examples of dendritic cell therapy include AGS-004. CCR5 gene editing agents include SB-728T. CCR5 gene inhibitors include Cal-1. In some embodiments, C34-CCR5/C34-CXCR4 expressing CD4-positive T-cells are co-administered with the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments. In some embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments are co-administered with AGT-103-transduced autologous T-cell therapy or AAV-eCD4-Ig gene therapy.

    Gene Editors

    [0225] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a gene editor, e.g., an HIV targeted gene editor. In various embodiments, the genome editing system can be selected from the group consisting of: a CRISPR/Cas9 complex, a zinc finger nuclease complex, a TALEN complex, a homing endonucleases complex, and a meganuclease complex. An illustrative HIV targeting CRISPR/Cas9 system includes without limitation EBT-101.

    CAR-T-Cell Therapy

    [0226] In some embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein can be co-administered with a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen binding domain. The HIV antigen include an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, the CD4-induced binding site on gp120, N glycan on gp120, the V2 of gp120, the membrane proximal region on gp41. The immune effector cell is a T-cell or an NK cell. In some embodiments, the T-cell is a CD4+ T-cell, a CD8+ T-cell, or a combination thereof. Cells can be autologous or allogeneic. Examples of HIV CAR-T include convertibleCAR-T, VC-CAR-T, anti-CD4 CART-cell therapy, autologous hematopoietic stem cells genetically engineered to express a CD4 CAR and the C46 peptide.

    TCR-T-Cell Therapy

    [0227] In certain embodiments, the anti-HIV gp120 V3 glycan directed antibodies or antigen-binding fragments described herein are combined with a population of TCR-T-cells. TCR-T-cells are engineered to target HIV derived peptides present on the surface of virus-infected cells.

    [0228] 6. Kits

    [0229] Further provided are kits for performing the diagnostic and treatment methods, as described herein. In some embodiments, the kit comprises primers for amplifying and sequencing at least the gp120 V3 glycan region of HIV species in a biological sample. In some embodiments, the kit comprises a suite or set of nested primers for amplifying and sequencing at least the gp120 V3 glycan region of HIV species in a biological sample. In some embodiments, the kit comprises a pair of primers or a set of nested primers for amplifying and sequencing the full length gp120. In some embodiments, the kit comprises sample preparation, nucleic acid quantification, amplification and/or sequencing reagents, e.g., nucleic acid isolation reagents to isolate RNA and/or DNA, protein denaturation solvents, buffers, dNTPs, reverse transcriptase enzyme, polymerase enzyme, and/or detection labels. In some embodiments, the kit comprises library preparation reagents, e.g., barcode reagents and/or target specific primers. In some embodiments, the kit comprises an analysis guide and/or software, e.g., to facilitate practicing the diagnostic methods, described herein. In some embodiments, the kit comprises instructions for sequencing at least the gp120 V3 glycan region of HIV species in a biological sample and detecting or identifying HIV species expressing a gp120 comprising: a glycosylated asparagine at the position corresponding to amino acid residue position 332 (N332glycan), an aspartate at the position corresponding to amino acid residue position 325 (D325), and one or more amino acid of: a threonine at the position corresponding to amino acid residue position 63 (T63), a leucine at the position corresponding to amino acid residue position 179 (L179), a threonine at the position corresponding to amino acid residue position 320 (T320), and a histidine at the position corresponding to amino acid residue position 330 (H330), wherein the amino acid positions are with reference to SEQ ID NO: 4 (i.e., residues 1-511 of NCBI Ref Seq No. NP_057856.1), as described herein.

    [0230] In one embodiment, the kit comprises one or more pharmaceutical packs comprising one or more containers (e.g., vials, ampules, pre-loaded syringes) containing one or more of the ingredients of the pharmaceutical compositions described herein, such as an antibody, or antigen-binding fragment thereof, against the HIV gp120 V3 glycan region, or one or more polynucleotides encoding such antibody or antigen-binding fragment, as provided herein. In some instances, the kits contain a pharmaceutical composition described herein. In some embodiments, the kit comprises one or more containers comprising an antibody, or antigen-binding fragment thereof, against the HIV gp120 V3 glycan region, or one or more polynucleotides encoding such antibody or antigen-binding fragment, in an aqueous solution or in lyophilized form. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

    EXAMPLES

    [0231] The following examples are offered to illustrate, but not to limit the claimed invention.

    Example 1

    Identification of HIV-Infected Patients Responsive to Therapy with an Anti-HIV gp120 V3-Glycan Directed Antibody or Antigen-Binding Fragment Thereof

    [0232] This Example demonstrates identification of Env genotypes associated with viral susceptibility to neutralization by PGT121 and its derivative, GS-9722 (elipovimab), for prescreening of HIV-infected subjects for susceptibility to PGT121/GS-9722.

    [0233] High level of sequence diversity in the HIV envelope gene makes prescreening of subjects in clinical trials for broadly neutralizing antibodies (bNAbs) attractive to increase the likelihood of a high response rate. To identify an Env genotype that is predictive of viral susceptibility to PGT121 and GS-9722, we examined the PGT121 and GS-9722 neutralization data and corresponding Env sequence for 206 clade B Envs.

    [0234] GS-9722 is a engineered variant of PGT121 that maintains the same neutralization activity as PGT121, as evidenced by a highly statistically significant correlation of PGT121 and GS-9722 neutralization IC50s among 397 HIV strains tested with PGT121 and GS-9722 (r.sup.2=0.9698, P<0.0001). We therefore combined the GS-9722 neutralization data obtained on 140 clade B Envs isolated from viremic subjects enrolled in Gilead-sponsored clinical trials, with publicly-available PGT121 neutralization data obtained from the Los Alamos HIV Sequence Database (n=66) to increase the statistical power.

    [0235] Full length Env amino acid sequences were aligned using ClustalW and manually adjusted upon visual inspection. To identify genotypes associated with sensitivity to neutralization by PGT121/GS-9722, we compared the frequency of amino acids and potential N-linked glycosylation sites (PNGS) at each residue among PGT121/GS-9722-sensitive viruses to the frequency in PGT121/GS-9722-resistant viruses by Fisher's exact test. An N-linked glycosylation motif is NXS/T, where X is any residue except proline. Neutralization sensitivity to PGT121/GS-9722 was defined as IC50<1 g/mL. For residues that were statistically significantly associated with sensitivity to PGT121/GS-9722, the positive predictive value (PPV; i.e., probability Env is sensitive to PGT121/GS-9722 when genotype is present) and sensitivity (i.e., probability that the genotype is present when Env is sensitive to PGT121/GS-9722) were calculated as described below:

    TABLE-US-00012 TABLE 1 2 2 Table Used to Calculate PPV, NPV, Sensitivity and Specificity for Genotypic Determinants of PGT121/GS-9722 Sensitivity PGT121/GS-9722 sensitive PGT121/GS-9722 resistant Genotype (+) a c Genotype () b d

    [00001] PPV = a a + c Sensitivity = a a + b

    [0236] A Mann-Whitney test was also applied to identify determinants of susceptibility independent of the 1 g/mL cut-off for defining Envs as susceptible vs resistant.

    [0237] Residues that were statistically associated with susceptibility to PGT121/GS-9722 and/or previously are reported to be associated with PGT121 susceptibility are listed in Table 2, ranked by descending PPV. Of the residues previously reported to confer susceptibility to PGT121, 3071, 295 PNGS and 300 PNGS were not statistically associated with susceptibility to PGT121/GS-9722 in this clade B dataset. We identified many previously unreported residues to be significantly associated with susceptibility to PGT121/GS-9722.

    TABLE-US-00013 TABLE 2 Individual genotypes associated with susceptibility to PGT121/GS-9722 neutralization among clade B Envs Fisher's Exact Mann-Whitney Virus genotype.sup.1 PPV Sensitivity P value P value K677 78.8 31.8 0.005 0.002 not_W17 75.3 47.3 0.0031 0.0001 332 glycan* 75.1 98.4 0.0001 0.0001 not_R747 74.4 51.9 0.0023 0.0075 insertion_321.01 73.8 45.7 0.0118 0.0365 E429 71.7 80.6 0.0001 0.0001 Q442 70.7 50.4 0.0423 0.0155 T63 69.6 86.8 0.0002 0.0009 R335 69.3 47.3 0.1092 0.0035 H330* 68.9 87.6 0.0003 0.0009 i165 68.3 66.7 0.0397 0.1486 D325* 67.3 89.1 0.0037 0.0033 T320 66.5 86.0 0.0266 0.0193 L179 66.0 81.4 0.0855 0.0123 S393 65.2 82.9 0.1529 0.0165 301 glycan* 64.5 98.4 0.0158 0.0147 i307* 64.1 91.5 0.2443 0.5291 295 glycan* 63.9 76.7 0.617 0.1188 N300* 61.9 74.4 0.7423 0.0629 no selection 62.6 100 na na .sup.1Virus genotype, indicates the presence of specific amino acid residues translated from the HIV envelope gene *Residue reported in the literature to confer susceptibility to PGT121 neutralization (Julg et al, Sci Transl Med. (2017) 9(408)).

    [0238] Since an epitope is comprised of more than one residue, combinations of genotypic determinants that were statistically associated with susceptibility to PGT121/GS-9722 were evaluated to see if combining individual genotypic determinants improved the PPV by preferentially enriching true positives over false positives. Consideration was also given to sensitivity since genotypes with low sensitivity will require screening of a larger number of subjects in order to enroll sufficient number of subjects in clinical trials.

    [0239] The combination genotypes that provided the highest PPV and sensitivity are listed in Table 3 and displayed in FIG. 1. Several combination genotypes that incorporated previously unreported genotypes associated with susceptibility to PGT121/GS-9722 neutralization provided higher PPV than was achievable using only previously described genotypes. The highest PPV obtained was 98.4% (for viruses containing the amino acids N332 glycan/D325/H330/T63/T320/L179), which represents a 57% increase over the positive predictive value of 62.6% with no genotype selection.

    TABLE-US-00014 TABLE 3 Individual and combination genotypes associated with susceptibility to PGT121/GS-9722 neutralization among clade B Envs Fisher's Exact Mann-Whitney Virus genotype.sup.1 PPV Sensitivity P value P value N332glycan/D325/H330/T63/T320/L179 98.4 47.3 0.0001 0.0001 N332glycan/D325/H330/T63/T320 93.7 57.4 0.0001 0.0001 N332glycan/D325/H330/T320/L179 93.3 54.3 0.0001 n.a. N332glycan/D325/H330/T63 91.6 67.4 0.0001 0.0001 N332glycan/D325/H330/T320 86.1 67.4 0.0001 0.0001 332PNGS/301PNGS/D325/H330* 83.9 76.7 0.0001 0.0001 N332glycan/D325/H330* 83.5 78.3 0.0001 0.0001 N332glycan/D325* 80.7 87.6 0.0001 0.0001 glycan332 75.1 98.4 0.0001 0.0001 glycan301 64.5 98.4 0.0158 0.0147 D325 67.3 89.1 0.0037 0.0033 H330 68.9 87.6 0.0003 0.0009 T63 69.6 86.8 0.0002 0.0009 T320 66.5 86 0.0266 0.0193 L179 66 81.4 0.0855 0.0123 no selection.sup.2 62.6 100 n.a. n.a. .sup.1Virus genotype, indicates the presence of specific amino acid residues translated from the HIV envelope gene .sup.3None, indicates 206 subtype B viruses without selection for specific amino acids in the HIV envelope gene *indicates genotypes comprised of residues previously reported in the literature to be associated with susceptibility to PGT121. See, e.g., Julg et al, Sci Trans/Med. (2017) 9(408).

    [0240] The combination genotypes for PGT121/GS-9722 in Table 3 for clade B were used to determine PPV, sensitivity and prevalence for clade A (Table 4) and clade C (Table 5) using neutralization data and corresponding Env sequence for 66 clade A Envs and 258 clade C Envs. The clade A and clade C datasets were publicly-available data obtained from the Los Alamos HIV Sequence Database. The highest PPV obtained for clade A was 93.8% (for viruses containing the amino acids N332glycan/D325/H330/T320/L179), which represents an 88% increase over the positive predictive value of 50% with no genotype selection. The highest PPV obtained for clade C was 89.3% (for viruses containing the amino acids N332glycan/D325/H330/T320/L179), which represents a 53% increase over the positive predictive value of 58.5% with no genotype selection.

    TABLE-US-00015 TABLE 4 Individual and combination genotypes associated with susceptibility to PGT121 neutralization among clade A Envs Virus genotype.sup.1 PPV Sensitivity Prevalence N332glycan/D325/H330/T63/T320/L179 92.9 39.4 21.2 N332glycan/D325/H330/T63/T320 70.8 51.5 36.4 N332glycan/D325/H330/T63 69.2 54.6 39.4 N332glycan/D325/H330/T320/L179 93.8 45.5 24.2 N332glycan/D325/H330/T320 73.1 57.6 39.4 N332glycan/D325/H330 71.4 60.6 42.4 N332glycan/D325 68.8 66.7 48.5 glycan332 68.4 78.8 57.6 no selection.sup.2 50 100 100 .sup.1Virus genotype, indicates the presence of specific amino acid residues translated from the HIV envelope gene .sup.2None, indicates 66 clade A viruses without selection for specific amino acids in the HIV envelope gene

    TABLE-US-00016 TABLE 5 Individual and combination genotypes associated with susceptibility to PGT121 neutralization among clade C Envs Virus genotype.sup.1 PPV Sensitivity Prevalence N332glycan/D325/H330/T63/T320/L179 81.8 6.0 4.3 N332glycan/D325/H330/T63/T320 85.7 8.0 5.4 N332glycan/D325/H330/T63 86.7 8.6 5.8 N332glycan/D325/H330/T320/L179 89.3 44.4 29.1 N332glycan/D325/H330/T320 88.0 62.9 41.9 N332glycan/D325/H330 86.6 72.9 49.2 N332glycan/D325 81.1 82.1 59.3 glycan332 73.7 92.7 73.6 no selection.sup.2 58.5 100 100 .sup.1Virus genotype, indicates the presence of specific amino acid residues translated from the HIV envelope gene .sup.2None, indicates 258 clade C viruses without selection for specific amino acids in the HIV envelope gene

    [0241] The prevalence of individual amino acids (T63, L179, T320, D325, H330, N332, NotP333 and S/T334) used in the PGT121/GS-9722 combination genotypes were determined for the clade A, clade B and clade C virus sequences (Table 6). All amino acids show prevalence above 60% in clade B, in clade A except for L179 (51.5%), and in clade C except for T63 (10.1%).

    TABLE-US-00017 TABLE 6 Prevalence of individual amino acids in clade A, clade B and clade C viruses Prevalence.sup.1 Position clade A clade B clade C T63 84.8 78.2 10.1 L179 51.5 77.2 63.2 T320 89.4 81.1 86 D325 80.3 83 80.2 H330 72.7 79.6 75.2 N332 66.7 86.9 83.7 NotP333 100 100 100 S/T334 62.1 84 77.6 .sup.1Analysis based on the 66 clade A, 206 clade B and 258 clade C viruses from the PGT121/GS-9722 datasets

    [0242] 10-1074 is a broadly neutralizing antibody that targets the V3 glycan region of HIV gp120 and that is related to PGT121/GS-9722. See, e.g., Mouquet, et al., Proc Natl Acad Sci USA. 2012 Nov. 20; 109(47):E3268-77 and Walker, et al., Nature. 2011 Sep. 22; 477(7365):466-70. The combination genotypes for PGT121/GS-9722 in Table 3 were used to determine PPV, sensitivity and prevalence for 10-1074 using neutralization data and corresponding Env sequence for 315 clade B Envs (Table 7). The 315 clade B dataset consisted of 143 clade B Envs isolated from viremic subjects enrolled in Gilead-sponsored clinical trials and 172 clade B Envs from publicly-available data obtained from the Los Alamos HIV Sequence Database. The highest PPV obtained was 100% (for viruses containing the amino acids N332glycan/D325/H330/T63/T320/L179), which represents a 61% increase over the positive predictive value of 62.2% with no genotype selection.

    TABLE-US-00018 TABLE 7 Individual and combination genotypes associated with susceptibility to 10-1074 neutralization among clade B Envs Virus genotype.sup.1 PPV Sensitivity Prevalence N332glycan/D325/H330/T63/T320/L179 100.0 38.8 24.1 N332glycan/D325/H330/T63/T320 99.0 51.5 32.4 N332glycan/D325/H330/T63 98.5 65.8 41.6 N332glycan/D325/H330/T320/L179 96.8 46.4 29.8 N332glycan/D325/H330/T320 94.4 59.7 39.4 N332glycan/D325/H330* 93.6 75.0 49.8 N332glycan/D325 92.2 84.7 57.1 glycan332 86.9 98.0 70.2 no selection.sup.2 62.2 100 100 .sup.1Virus genotype, indicates the presence of specific amino acid residues translated from the HIV envelope gene .sup.2None, indicates 315 clade B viruses without selection for specific amino acids in the HIV envelope gene

    [0243] Subsequently, the highest scoring genotypic algorithms (Table 3) were applied to analyze pre-ART plasma samples from HIV infected individuals from the Zurich Primary HIV Infection Cohort Study (ZPHI) to predict whether they would be sensitive to GS-9722 treatment. A total of 92 individual plasma samples were analyzed in a NGS assay of the HIV envelope gene (GenoSure HIV Envelope RNA Assay, Monogram Biosciences, South San Francisco, Calif.). Subjects were characterized as positive for a given genotype if the derived virus sequences contained the amino acids specified by the algorithm without sequence variability (zero sequence variability on the specified positions). With these criteria, 47/92, 37/92, 32/92, 27/92, 22/92, and 16/92 subjects were predicted to be sensitivity to GS-9722 (FIG. 1) with corresponding positive predictive values of 80.7%, 83.5%, 86.1%, 91.6%, 93.7%, and 98.4%, respectively (Table 3). For clade B infected subjects (59 of the 92 subjects), 35/59, 27/59, 22/59, 23/59, 18/59, and 12/59 were predicted to be sensitivity to GS-9722 (FIG. 2) with corresponding positive predictive values of 80.7%, 83.5%, 86.1%, 91.6%, 93.7%, and 98.4%, respectively (Table 3).

    [0244] The 100% conservation (zero sequence variability on the specified positions) of the individual amino acids (T63, L179, T320, D325, H330, N332, NotP333 and S/T334) used in the combination genotypes for GS-9722 sensitivity prediction was determined for pre-ART plasma samples for all subjects (n=92) and for the subset of subjects infected with clade B (n=59), (Table 8).

    TABLE-US-00019 TABLE 8 100% conservation of individual amino acids in ZPHI subjects 100% conservation (% of subjects) Position All subjects Clade B infected subjects T63 64 75 L179 59 58 T320 86 85 D325 70 73 H330 65 71 N332 76 85 NotP333 100 100 S/T334 74 85 .sup.1Analysis based on 92 (all subjects) and 59 (clade B subjects) pre-ART plasma samples from ZPHI individuals

    [0245] To confirm the genotypic prediction for sensitivity to GS-9722, virus swarms from pre-ART plasma samples from ZPHI were cloned and evaluated in a GS-9722 neutralization assay (PhenoSense HIV Entry Assay, Monogram Biosciences, South San Francisco, Calif.). Virus was derived from 29 clade B samples with positive predictive values of 80.7% or higher. The derived viruses were characterized as GS-9722 sensitive when IC50s were 1 g/ml or below. With these criteria, 25/29, 20/22, 16/18, 18/20, 14/16, and 10/11 viruses were confirmed to be sensitivity to GS-9722 (FIG. 2) with corresponding positive predictive values of 80.7%, 83.5%, 86.1%, 91.6%, 93.7%, and 98.4%, respectively (Table 3).

    [0246] To further confirm the genotypic prediction and phenotypic sensitivity to GS-9722, 20 individual viruses from 4 virus swarms from pre-ART plasma samples from ZPHI were subcloned and evaluated in a GS-9722 neutralization assay (PhenoSense HIV Entry Assay, Monogram Biosciences, South San Francisco, Calif.). All individual viruses were sensitive to GS-9722 with comparable IC50s to the swarm virus (FIG. 4).

    [0247] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.