Development of HSV Vectors as AIDS Vaccines

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The HIV epidemic continues unabated, in particular in sub-Saharan Africa and parts of Asia. Despite the numerous AIDS vaccines under consideration, only one has been tested in phase III trials, the gp120 envelope protein vaccine, and it showed no protective effect. This project proposes to test and develop novel replication-defective herpes simplex virus vaccine vectors, which have been shown in previous work to induce both T cell and antibody responses, including neutralizing antibodies, against SIV proteins in immunized rhesus macaques. Furthermore, the immunized macaques showed reduced viral loads after intravenous pathogenic SIV challenge. These HSV recombinant vectors are among only a few immunization approaches that have elicited any protection in rhesus macaques against pathogenic SIVmac239 challenge infection either by mucosal SIV challenge or intravenous SIV challenge. Therefore, the continued development of these vectors is highly justified at this point. Nevertheless, the level of transgene expression and immunogenicity of the vector and expressed antigens needs to be optimized. The proposed research in this application tests various modifications that should enhance this vector system and further the development of this novel vaccine vector system. In this proposal our specific aims are 1. To construct improved HSV-1 recombinant vaccine vectors in the HSV-1 d106 strain by testing the hypothesis that increasing expression of HIV gag protein by d106 vectors will increase CD8+ T cell immune responses in mice, by testing the hypothesis that mutating the V1/V2 loops of HIV env or mutating the glycosylation sites on env protein will enhance the antibody responses to env, by testing the hypothesis that co-expression of a Toll-like receptor ligand, the SARS virus spike protein, by the d106 vector will increase immune. 2. To test the hypothesis that mucosal immunity can be induced by immunization at various mucosal sites. 3. Test the hypothesis that glycoproteins on the HSV virion play a role in immune evasion so that HSV vaccine vectors are efficacious in HSV-immune mice. 4. Define the biological properties of the HSV c/106 recombinant vectors by testing persistence of vector DNA, neurovirulence, latent infection, and safety in immunodeficient animals.