The goal of this project is to use herpes simplex virus (HSV) as a vaccine vector to express simian immunodeficiency virus (SIV) proteins as a new approach to elicit immunity against SIV in inoculated animals. We have isolated three HSV-1 recombinants that express SIV env protein. In this application we want to exploit several recent important observations that promise approaches to make better to promise approaches to make better vectors. We propose to make HSV type 2 recombinant strains that express SIV and HIV env and gag from rev-independent mutant genes provide by Dr. George Pavlakis. Our hypothesis is that herpesviruses can be genetically modified to provide safe viral vectors for AIDS vaccines that possess some of the same biological properties as AIDS viruses. First, herpes viruses, like HIV replication-defective HSV strains seem to induce durable immune responses in mouse model systems. Second, herpes viruses activate a strong cellular immune response without the risk of killing T cells. Thus, our hope is that the herpesvirus recombinant vectors can induce a robust cellular response against AIDS virus antigens that is continually activated and eliminated any HIV or SIV infected cell soon after infection. In this application our specific aims are 1) To construct and characterize HSV-2 recombinant strains that are replication-defective and express SIV env and gag from rev-independent genes, 2) To construct and characterize HSV-2 thymidine kinase-negative recombinant strains that are replication-competent and express SIV env and gag, 3) To identify HSV- 2 genes other than TK whose inactivation leads to HSV-2 mutant strains that are attenuated, but competent for establishment of and reactivation from latent infection in mice, 4) To use the mutant strains identified in specific aim 3 and to construct HSV-2 recombinant strains that are attenuated, replication-competent and latency competent and express SIV env and gag, and 5) To isolate HSV-2 recombinant strains expressing human immunodeficiency virus (HIV) gag and/or env.
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