The long-term goal of this proposal is to define the contribution of two major components of the innate immune system (accessory and Natural Killer cells) in controlling HIV replication and thereby modifying disease progression. The short-term goal of this project is to address the consequences of immune reconstitution following antiretroviral therapy on innate immunity with particular emphasis on correlates of DC and NK cell function with viral suppression. Based on our preliminary data on NK and DC dysfunction during HIV replication in vivo and: (1) the observed effects of antiretroviral therapy on DC and NK cell subsets, (2) the inverse correlation between viral load and DC subsets in untreated HIV positive subjects and (3) our observations of augmented NK lytic activity by activated DC, we propose to perform longitudinal analysis and mechanistic experiments on DC/HIV interactions to test the hypothesis that HAART- mediated viral suppression restores mature NK and DC subsets necessary to activate innate mechanisms of antiviral control through lysis of infected cells, To test our hypothesis, we will characterize the in-vivo and in vitro interactions between MV infection and innate immunity cell function by (1) longitudinal analysis of the consequences of HAART- mediated suppression (i.e., recovery of function as a correlate of viral suppression) or known clinical outcomes (Multiple AIDS Cohort Study National Repository) and (2) in vitro analysis of the effects of HIV on APC subsets that bear on NK activity. Specifically, we propose to determine the significance of our preliminary observations by addressing the association between innate cell function and HIV infection by: (1) Defining the phenotypic and functional changes in APCs (monocytes and DC) and NK cells in seroconverters with fast or delayed disease progression and in chronically infected patients starting HAART at different CD4 count stages through longitudinal analysis of: changes in DC (MDCIPDC) and mature CD161KD56 NK cell subsets; changes in accessory cell-surface expression of functional molecules (CD40, CD54, MHC Class I, CD1 IC, CD16, CD80, CD86) and activation molecule CD95; changes in APC viability and APC-dependent endocytosis, cytokine secretion (IL- 12 and IFN-a ), and allogeneic responses; and changes in activated CD161KD56 NK cytokines, lytic molecules (granzyme, perforin) and cytotoxic activity. (2) Defining the mechanisms and consequences of APC impairment and loss in HIV-1 infection by analysis of in vivo-derived MDC and PDC subsets exposed to HIV-1 and analyzed for viability, function, infection as part of an overall aim to define how HIV interactions with DC affect NK function. This study represents a hypothesis-driven collaborative effort by The Wistar Institute, the Infectious Disease Division of the University of Pennsylvania Hospital, Philadelphia FIGHT, Schering-Plough and the Multiple AIDS Cohort Study
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