Direct measurement of T-cell turnover in SIV infection and following pharmacologic and immunotherapeutic interventions. We have hypothesized that the evolution of immune hyporesponsiveness in HIV/SIV infection can be explained by the dynamics of TR cell replacement. Several indirect lines of evidence point to a process in which chronic virus mediated loss of CD4+ T cells is countered by T cell replacement which is successful at first, but ultimately fails. The consequent immune deficiency culminates in progression to clinical AIDS or SAIDS. It is the purpose of this proposal to directly test the hypothesis that late stage disease is characterize by a high rate of de novo generation of replacement T cells (CD4+ and CD8+), and a high apoptosis rate, the consequence of which is the gradual dominance of newly generated short lived naive T cells. We hypothesize that erosion of the CD4+ T cell memory compartment results in T lymphopoiesis with rapid turnover kinetics: the majority of newly generated mature T cells fail to receive survival signals (provided by preexisting CD4+ memory cells and dendritic cells) and apoptose before they can undergo antigen driven selection and maturation to effector cells. This hypothesis can only be tested by direct measurement of T-cell turnover and determination of the phenotype, functional capacity and fate of replacement T cells. To this end we propose to apply multi-parametric flow cytometric methods suitable for the simultaneous determination of cell surface immunophenotype, growth and apoptosis kinetics to the SIV/rhesus macaque model. Turnover will be measured in animals before SIV infection, at early and late stages of infection, and after chemo- and adjunctive immuno-therapy. A second and related goal of this project is to sequentially monitor the ability of infected and treated animals to mount antigen specific recall and primary T cell and antibody responses. The proposed studies are designed to directly interface with projects I and II of this program project, in which two distinct approaches to SIV-specific adjuvant immunotherapy will be tested.
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