COMBINED VACCINE STRATEGIES FOR THE PREVENTION OF AIDS

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The long-term objective of this program is to develop and optimize novel strategies for prophylactic immunization against the human immunodeficiency virus (HIV) using novel recombinant viral vector vaccines. The combined programs of this NCVDG have four specific recombinant viral vector vaccines. The combined programs of this NCVDG have four specific aims: 1. Construction and biochemical analyses of novel HIV and SIV vaccines, based on live recombinant poxvirus vectors, live recombinant adeno- associated virus vectors, and non infectious HIV and SIV-like particles derived from recombinant poxviruses. 2. Comparison of the safety and efficacy of individual vaccines and combinations of vaccines in rodents and primates. 3. Quantitative and qualitative analyses of SIV-specific humoral and cellular immune responses in primates immunized with individual or combined vaccines. 4. Analysis of the breadth, magnitude and natural variation of humoral and cellular immune responses in hosts naturally infected with HIV and SIV. Novel features of this application include the use of adeno-associated virus (AAV) as a gene transfer vector. AAV is a replication-defective parvovirus with unique features that make it attractive as a vector for the stable delivery of foreign DNA to cells. In addition, we will construct and test new recombinant poxviruses, including fowlpox virus and swinepox virus, as potentially safer alternatives to the use of vaccina virus. Recombinant viruses will be constructed expressing a variety of novel genes. Such genes will include genes from clinically relevant HIV strains derived from recent patient isolates, auxiliary genes in addition to the major antigen-encoding genes of SIV and HIV, and the inclusion of cytokine genes to attempt to increase safety and/or increase vaccine which can be used to prevent maternal-infant transmission of HIV. SIV particle vaccines will be studied in neonatal rhesus macaques for immunogenicity and primary induction of cytotoxic lymphocytes. Similar studies will be carried out with HIV particle vaccines in rabbits. The most promising of these approaches will be incorporated into candidate HIV vaccines destined for clinical trials in humans.