Elucidation of the mechanisms of T cell depletion caused by HIV infection, and the reasons why the regenerative capacity of the host immune system is ultimately unable to compensate for virus-induced damage represent central unresolved issues in AIDS pathogenesis. However, until very recently, it has not been possible to measure T cell proliferation and destruction rates directly in humans in vivo. Such information is critical to define T cell population dynamics during HIV infection and clarify the extent to which accelerated destruction of CD4+ T cells or their diminished production, or both, account for progressive depletion of CD4+T numbers. In addition to defining the immune homeostatic defect in AIDS, techniques that accurately and safely enable measurement of T cell population dynamics in humans will provide essential measures to gauge the efficacy of therapeutic interventions intended to restore T cell numbers and function in persons with HIV infection. Recently, a stable isotope/mass spectrometric (SI/MS) method to measure lymphocyte turnover rates in humans has been developed; but the optimal parameters for use of this method have not yet been defined. Furthermore, the SI/MS method has yet to be directly compared to other measures of T cell proliferation applied previously to the study of AIDS pathogenesis in humans or animals models. To help advance technical approaches for the study of T cell population dynamics in humans and to provide basic insights into model systems where host compensatory responses do keep up with chronic immunodeficiency virus infection, we propose to (1) adapt the SI/MS technique to the study of non-human primate models of AIDS, (2) directly compare the SI/MS method to other methods that have been applied to study T cell turnover in AIDS including bromodeoxyuridine labeling, Ki67 staining for proliferation-associated nuclear antigens and measurement of T cell receptor deletion circles that mark new thymic emigrant s and (3) apply these new methods to define T cell population dynamics in sooty mangabey monkeys where normal CD4+ T lymphocyte numbers and functions are preserved despite active virus replication and associated destruction of infected cells, and limited cellular antiviral immune responses seen. Rigorous comparison studies will be conducted in non-human primate models of AIDS because they cannot practically or ethically be conducted in humans. However, the results of these studies should help guide the optimal use of methods to assess lymphocyte population dynamics in humans, provide insights into the failure of immune compensatory mechanisms in HIV infection, and may help suggest new ways to prevent or reverse immune system damage in persons with HIV infection. FUNDING NIH / NIAID $658,000 9/30/98 - 9/29/00 PUBLICATIONS NONE P51RR00165-38 1/1/1998 - 12/31/1998 Yerkes Regional Primate Research Center
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