The present invention provides CD8+ T cells comprising multi-specific T cell receptors and methods for making the same.

The present invention relates to a base editing compound comprising or consisting of (a) a Cas protein, and, covalently connected therewith; (b) a nucleobase-modifying enzyme, wherein the covalent connection of (a) and (b) is (i) direct; (ii) provided by a peptide comprising at least one Pro residue, said peptide having a length between 1 and 20 preferably between 1 and 15 amino acids; or (iii) provided by a non-peptidic linker, said non-peptidic linker being a small organic molecule comprising one or more double bonds, one or more triple bonds, and/or one or more aromatic rings.

The invention features compositions and methods for modifying a polynucleotide (e.g., DNA) using a nucleobase editor comprising a first DNA binding protein domain that is catalytically inactive, a domain having base editing activity, and a second CDNA binding protein domain having nickase activity. The invention also features a fusion protein comprising a domain having base editing activity (e.g., cytidine deaminase or adenosine deaminase), and two nucleic acid programmable DNA binding protein domains (napDNAp), a first napDNAbp comprising nickase activity and a second napDNAbp that is catalytically inactive, where at least the two napDNAbps are joined by a linker, as well as related methods for using such base editors, and kits comprising the base editors.

CMV vectors that lack active UL128, UL130, UL146 and UL147 proteins that may also comprise one or more microRNA regulatory elements (MRE) that restrict expression of the CMV are provided. Immunization with CMV vectors having the described features allows selection of different CD8+ T cell responses—CD8+ T cells restricted by MHC-Ia, MHC-II, or by MHC-E.

Particular aspects provide for use of the β-herpesvirus Cytomegalovirus (CMV: e.g., RhCMV and HCMV) as a uniquely evolved “vector” for safely initiating and indefinitely maintaining high level cellular and humoral immune responses (against, e.g., HIV, SIV, TB, etc.). Particular aspects provide a method for treatment or prevention of, e.g., HIV, SIV or TB, comprising infection of a subject in need thereof with at least one recombinant CMV-based vector (e.g., HCMV or RhCMV) comprising an expressible HIV/SIV/TB antigen or a variant or fusion protein thereof. In particular embodiments of the method, infection is of an immunocompetent, HCMV or RhCMV seropositive subject. Additional aspects provide for RhCMV- and HCMV-based vaccine vectors, and versions thereof with suicide or safety means. Further aspects provide pharmaceutical compositions comprising the inventive CMV-based vaccine vectors.

The invention provides a bidirectional hCMV-rhCMV promoter and recombinant vectors and recombinant virus comprising the bidirectional hCMV-rhCMV promoter operably linked to a first transgene in one direction and to a second transgene in the opposite direction. The invention also provides methods of making and using such recombinant vectors and recombinant virus.

Provided herein are methods and compositions for treatment of Batten disease. Such compositions include a recombinant adeno-associated virus (rAAV), said rAAV comprising an AAV capsid, and a vector genome packaged therein, said vector genome comprising (a) an AAV inverted terminal repeat (ITR) sequence; (b) a promoter; (c) a CLN2 coding sequence encoding a human TPP1; (d) an AAV 3′ ITR.

Particular aspects provide for use of the β-herpesvirus Cytomegalovirus (CMV: e.g., RhCMV and HCMV) as a uniquely evolved “vector” for safely initiating and indefinitely maintaining high level cellular and humoral immune responses (against, e.g., HIV, SIV, TB, etc.). Particular aspects provide a method for treatment or prevention of, e.g., HIV, SIV or TB, comprising infection of a subject in need thereof with at least one recombinant CMV-based vector (e.g., HCMV or RhCMV) comprising an expressible HIV/SIV/TB antigen or a variant or fusion protein thereof. In particular embodiments of the method, infection is of an to immunocompetent, HCMV or RhCMV seropositive subject. Additional aspects provide for RhCMV- and HCMV-based vaccine vectors, and versions thereof with suicide or safety means. Further aspects provide pharmaceutical compositions comprising the inventive CMV-based vaccine vectors.

The present disclosure relates to isolated polynucleotides and polypeptides, and related hepatitis B virus (HBV)vaccines. The present disclosure also relates to viral vectors for expressing such polypeptides, and which may be used in HBV vaccines, as well as methods of protecting a subject from HBV infection and methods of treating HBV in a subject comprising administering the polypeptides, vectors, or vaccines described herein. Methods of designing and producing an HBV vaccine comprising designing vaccine antigens to cover the diversity within a geographic area using an antigen amino acid sequence that efficiently covers the epitopes in the HBV genotypes present in the geographic area are also provided herein.

Certain embodiments of the invention provide a method of treating an excitable cell-related disease or condition in a mammal in need thereof, comprising administering to the mammal an effective amount of a vector comprising an expression cassette, wherein the expression cassette comprises a promoter operably linked to a nucleic acid encoding a subunit of a multimeric ion channel.