SPID#: 23 Despite almost 13 years of research on HIV and its role as the etiologic agent of AIDS, the mechanisms of pathogenesis remain mostly unknown. Specific in vitro effects have been identified that may contribute to the overall course of disease development. These include direct cell killing by HIV (syncytia formation); the induction of apoptosis; and the development of autoimmune responses; among others. While all of these effects have been observed in vitro and in vivo, the only mechanism consistently identified in vivo has been apoptosis. Because the exact time of infection can only be estimated in HIV-infected patients, a majority of the studies involving pathogenesis have been conducted during middle or late stage disease, at the least, following seroconversion. While much research has shown that a number of changes, including viral tropism changes, occur late, the early stages of infection may be as (or more) important in pathogenesis. The initial stages of infection involve viral amplification and seeding of lymphoid tissues, and can possibly dictate later effects, i.e. rapid or slow progression to disease. The SIV/macaque model represents the best system currently available to study AIDS pathogenesis, due to the striking genetic and biologic similarities. This model provides an excellent mechanism to investigate early pathogenesis of lentiviral infection. A recently characterized SIV isolate from a sooty mangabey (SIVsmmFGb) displays varied pathogenesis in pig-tailed and rhesus macaques. In pig-tailed macaques, this virus rapidly induces AIDS, whereas in rhesus macaques, disease progresses at a typically slower rate. The progression in pig-tailed macaques is associated with a high plasma viral load (as measured by p27 assay) an insufficient immune response (no anti-SIV antibody detected in most cases). In contrast, the rhesus macaques show a lower viral load, and make high levels of anti-SIV antibody. The pig-tailed macaques all succumbed to AIDS by 9 months post infection. In all cases, SIV- encephalitis was detected, illustrating the neurotropism of this virus. The differences in pathogenesis of this virus between rhesus and pig- tailed macaques should provide an excellent system for investigating determinants of AIDS pathogenesis.
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