The present disclosure provides compounds of Formula (I) or pharmaceutically acceptable salts thereof: (I) wherein, R1 to R6 and X are defined herein. Also provided are pharmaceutical compositions comprising these compounds, methods for treating Human Immunodeficiency Virus (HIV-1) in a subject in need thereof using these compounds or pharmaceutical compositions, and methods for stabilizing the state-1 conformation of the HIV-1 envelope glycoproteins using these compounds or pharmaceutical compositions.

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The present disclosure provides compounds of Formula (I) or pharmaceutically acceptable salts thereof: (I) wherein, R1 to R6 and X are defined herein. Also provided are pharmaceutical compositions comprising these compounds, methods for treating Human Immunodeficiency Virus (HIV-1) in a subject in need thereof using these compounds or pharmaceutical compositions, and methods for stabilizing the state-1 conformation of the HIV-1 envelope glycoproteins using these compounds or pharmaceutical compositions.

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This disclosure relates to HIV envelope proteins or envelope protein fragments, or trimeric complexes thereof which have uses in vaccination methods or therapeutic strategies. In certain embodiments, this disclosure relates to HIV envelope proteins or envelope protein fragments, or trimeric complexes thereof, comprising an arginine (R) at position 166, glutamine (Q) at position 170, and an amino acid histidine (H) at position 173. In certain embodiments, this disclosure relates to nucleic acids and recombinant vectors encoding said proteins.

This disclosure relates to HIV envelope proteins or envelope protein fragments, or trimeric complexes thereof which have uses in vaccination methods or therapeutic strategies. In certain embodiments, this disclosure relates to HIV envelope proteins or envelope protein fragments, or trimeric complexes thereof, comprising an arginine (R) at position 166, glutamine (Q) at position 170, and an amino acid histidine (H) at position 173. In certain embodiments, this disclosure relates to nucleic acids and recombinant vectors encoding said proteins.

A method of treating an RNA virus infection in a subject in need that includes administering a therapeutically effective amount of a heparanase inhibitor. The RNA virus includes SARS-CoV-1, SARS-CoV-2, HTLV-1, HIV-1, and any combination thereof. The heparanase inhibitor includes heparin, a heparin mimetic, or any combination thereof. In some aspects, the heparanase inhibitor is Roneparstat. In some aspects, the administration of the therapeutically effective amount of the heparanase inhibitor results in the inhibition of infection by the RNA virus and associated inflammatory cytokine production.

A method of treating an RNA virus infection in a subject in need that includes administering a therapeutically effective amount of a heparanase inhibitor. The RNA virus includes SARS-CoV-1, SARS-CoV-2, HTLV-1, HIV-1, and any combination thereof. The heparanase inhibitor includes heparin, a heparin mimetic, or any combination thereof. In some aspects, the heparanase inhibitor is Roneparstat. In some aspects, the administration of the therapeutically effective amount of the heparanase inhibitor results in the inhibition of infection by the RNA virus and associated inflammatory cytokine production.

The present disclosure relates to compositions and therapeutic methods for activating an immune response in a patient in need thereof. In a preferred embodiment, the subject methods and compositions are able to antagonize the activity of VISTA, a naturally occurring “checkpoint” protein which contributes to immune tolerance, optionally in combination with an antagonist of a second checkpoint pathway such as PD-1. For example, such methods and compositions may be suitable for preventing and treating colon cancer or another cancer. An exemplary VISTA antagonist, specifically, an anti-VISTA antibody, is demonstrated herein to activate an immune response against cancer cells in vitro and in vivo, thereby conferring protective anti-tumor immunity which decreased tumor burden. Additionally, an additive benefit was observed when a VISTA antagonist was used in combination with a second checkpoint protein antagonist, specifically, an antibody against PD-1 ligand (PD-L1).

The disclosure provides methods of treating viral infection using trispecific binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind a CD38 polypeptide (e.g., human and/or cynomolgus monkey CD38 polypeptides), a CD28 polypeptide, and a CD3 polypeptide.

The disclosure provides methods of treating viral infection using trispecific binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind a CD38 polypeptide (e.g., human and/or cynomolgus monkey CD38 polypeptides), a CD28 polypeptide, and a CD3 polypeptide.

The present invention provides monovalent antibodies with a long half-life when administered in vivo, methods of making such monovalent antibodies, pharmaceutical compositions comprising such antibodies, and uses of the monovalent antibodies.