ANIMAL MODELS FOR RETROVIRAL PATHOGENESIS, INFECTION AND PREVENTION OF INFECTION

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This project involves two major areas of research on human and non-human primate retroviruses: 1) molecular genetics applied to the study of in vivo pathogenesis in animal models for human immunodeficiency virus (HIV) and human T cell lymphotropic virus type-I (HTLV-I), as well as in naturally infected humans. These studies include: a) genetic manipulations of the HIV-2 and simian immunodeficiency virus (SIV) genome and study of their effect on viral infectivity and pathogenicity in vitro and in vivo in rhesus macaques. For example, we identified accessory genes (vpr, vif) which are essential in determining viral trophism and infectivity, and genetic determinants in the SIV envelope which regulate the cytocidal effect of SIV; b) molecular characterization of a field isolate of SIV (from Cercopithecus L'hoesti) and its use in rhesus macaques; c) development of an animal model rabbit and monkeys) for HTLV-I-associated neuropathy/tropic spastic paraparesis (HAM/TSP), the myelopathy associated to HTLV-I infection using field viral isolates from patients rather than culture adapted HTLV-I; and d) molecular analysis of viral expression and genetic drift in patients with HAM/TSP and adult T cell leukemia. 2) Development of a vaccine against HIV. The choice of the vector in which to express viral antigens might be crucial. We are pursuing several approaches in collaboration with various institutions which include oral vaccines (adenovirus based vaccine) attenuated salmonella typhi and BCG. These vaccines will be prepared with vector strains infectious for macaques and tested for efficacy in macaques first. Parenteral vaccines: Recombinant avipox and vaccinia viruses. Some of these vectors also need to be evaluated alone in monkeys to study the route and the kinetic infection. Various viral antigens (purified viral proteins or peptides) will be evaluated either alone or in conjunction with any of the above mentioned vectors.