Recent data from our collaborative group provide background for a new model of HIV pathogenesis that will be tested here. In this model, turnover of central memory (CM) CD4+ T cells is central to progressive cell losses of HIV infection. We propose that this is driven by interplay between indirect effects of HIV replication on the cytokine environment of secondary lymphoid tissues and in situ exposure to microbial TLR ligands translocated from the damaged gut. HIV replication is necessary but not sufficient to promote T cell turnover;microbial TLR ligands provide additional signals via two distinct mechanisms. First, they promote enhanced non-specific retention of effector CD8+ T cells in secondary lymphoid tissues by increasing expression of the C-type lectin CD69 that interferes with surface expression of sphingosine-1 phosphate receptors needed to permit exit of activated cells from lymph nodes. Sequestration of effector cells intensifies the cytokine "storm" in these tissues that results in explosive levels of common gamma chain receptor cytokines IL-2 and IL-15 that we have quantified at these sites. TLR ligands also activate CM T cells to lose characteristic resistance to death signals a resistance that is due to FOXOSa phosphorylation and inactivation. This results in heightened turnover and selective death of CM CD4+ T cells that drives the immune deficiency of HIV infection.
Our aims are: 1) To characterize the intercellular interactions and mechanisms whereby selected TLR ligands and common gamma chain receptor cytokines promote activation of central memory CD4+ and CD8+ T cells. This will be achieved by detailing the specific ARC requirements for T cell activation, by exploring selected gene expression patterns for signals characteristic of cell cycle progression, apoptosis and survival and to use these results to identify the pathways that render CM T cells in HIV infection more susceptible to death signals. 2) To establish in vitro models for bystander T cell activation and sequestration after exposure to TLR ligands and common gamma chain receptor cytokines in secondary lymphoid tissues. This will be accomplished first by defining the model using peripheral blood mononuclear cells in suspension and then confirming the model in lymph node histoculture experiments. 3) To identify the proximate causes of immune activation in chronic HIV infection. We will determine the levels of selected microbial TLR agonists, HIV RNA and bacterial PGN, LPS and DNA in the plasma of chronically HIV infected persons. Based upon the results of SpAim 1 experiments, we will develop a panel of flow based reagents that will characterize the signatures of bystander T cell activation that will be applied to ex vivo analyses of blood, lymph node and gut lymphocytes in chronic HIV infection.
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