DEVELOPMENT OF ANIMAL MODELS OF ACQUIRED IMMUNODEFICIENC

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We have isolated a simian T-cell lymphotropic virus from naturally infected healthy sooty mangabeys (Cercocebus atys), an African monkey, and have adapted this virus to in vitro growth in H9 cells. This new viral isolate is STLV-III-like because of serological cross-reactions with the core antigen of human T cell lymphotropic virus-III (HTLV-III) and the presence of typical lentiviral morphology by electron microscopy. Our STLV-III-like isolate is provisionally designated STLV-III (mangabey). In preliminary pathogenesis studies, 4 rhesus (Rh) (Macaca mulatta) and 1 African green monkey (AGM) (Cercopithecus aethiops) were inoculated with STLV-III (mangabey). Two of 2 rhesus tested have persistent viremia and T4/T8 ratio reversals along with clinical signs of retroviral infection (generalized lymphadenopathy and splenomegaly) at 12 and 22 weeks post-inoculation (pi) respectively. The AGM seroconverted for STLV-III, but is not viremic and is clinically healthy at 13 weeks pi. This proposal is directed toward developing a model for STLV-III (mangabey)-pathogenesis in monkeys by 1) inoculation of juvenile monkeys with the virus, 2) cloning and sequencing the virus, 3) preparing monoclonal antibodies to the core of STLV-III (mangabey), and 4) using monoclonal antibody and molecular probes to localize virus expression in infected lymphoid, salivary and neural tissues by immunohistochemistry and in situ hybridization. The importance of this work lies in the relationship of STLV-III (mangabey) to HTLV-III/LAV, the etiologic agent of human AIDS. Rh monkeys inoculated with STLV-III sometimes develop an AIDS-like disease. In contrast, African monkeys spontaneously infected with STLV-III are clinically normal. These studies will provide detailed knowledge of the biology of STLV-III infection in monkeys, will examine the relatedness of human and simian lentiviruses and will help illucidate questions in human AIDS pathogenesis, especially with respect to healthy carriers. This type of research requires a multi-disciplinary group of clinicians, pathologists, molecular biologists, and virologists. Such a group has been assembled at the California Primate Research Center and has established expertise in the pathogenesis of primate type D retroviral infections.