This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Peripheral blood CD4+ T cell counts are currently utilized as a measure to assess disease progression and need for antiretroviral therapy in HIV-infected patients. Simian immunodeficiency virus (SIV) infection of sooty mangabeys (Cercocebus atys) (a natural SIV host) does not result in progression to AIDS and is generally associated with maintenance of healthy CD4+ T cell levels despite levels of viral replication comparable to HIV-infected patients. Here, we utilize this primate lentiviral model, to demonstrate that multi-tropic (R5-X4-R8-using) SIV infection of mangabeys results in an extreme, persistent (5 years), and generalized CD4+ T cell loss (5 80 cells/ul blood) that has not been followed by progression to AIDS. This study demonstrates that generalized CD4+ T cell depletion from the blood and mucosal tissues is not sufficient to induce AIDS in this natural host species. Rather, AIDS pathogenesis appears to be the cumulative result of multiple aberrant immunologic parameters that include CD4+ T cell depletion, generalized immune activation, and depletion/dysfunction of non-CD4+ T cells. Therefore, these data provide a rationale for investigating multi-faceted therapeutic strategies to prevent progression to AIDS such that HIV+ humans can survive normal life spans analogous to what occurs naturally in SIV+ mangabeys.We are currently following 2 CD4-low mangabeys that have been infected for six years. They are perfectly healthy and revealing key insights into the mechanisms of HIV pathogenesis.
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