EXCEED THE SPACE PROVIDED. Highly active anti-retroviral therapy (HAART) has reduced mortality and morbidity from HIV infection. However, there is significant variability in the CD4+ T cell response to HAART with up to 25% of patients naive to anti-retroviral therapy having a clinically insignificant rise in peripheral CD4+ T cell count. Our preliminary data suggest a mechanism of chronic inflammation from HIV replication may be responsible for this variability by disruption of the reticular network and collagen formation in the T cell zone (TZ) of lymphatic tissues (LT),a unique niche where the pool of naive T cells is maintained, antigen presented, and proliferation occurs. Functionally this might cause abnormalities of cellular migration, T cell homeostasis, and lack of diffusion of cytokines and other signaling molecules. These observations have led us to form the hypothesis that ongoing rounds of HIV-1 replication in LT causes a progressive and destructive inflammatory reaction that alters the architecture and function of the TZ, the extent of which is directly related to the potential for successful restoration of the CD4+ T cell population with HAART. Our studies wilt determine if measurement of collagen as a function of architectural damage in the TZ more accurately predicts the change in CD4+ T cell count with ART than commonly used predictors (baseline CD4+ T cell count or plasma HIV RNA) and if the damage is reversible. We will complete functional studies to determine the kinetics of CD4+ T cell repopulation in both peripheral and lymphatic tissues by measuring the relative proportions of naive, memory, and effector CD4+ T cells in peripheral and LT at each time point to determine if there are reciprocal changes in these phenotypes in peripheral blood and LT that suggest redistribution as a mechanism for immune reconstitution. Through these studies we wish to elucidate the mechanism(s) for incomplete immune reconstitution. PERFORMANCE SITE ========================================Section End===========================================
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