A number of mechanisms have been put forward to explain the depletion of CD4 cells including cytopathic effect of the virus, reduced de novo production of T cells and killing of virally infected cells by HIV specific CD8+ T cells. Recently several groups have provided evidence indicating that the best correlate of the decrease in CD4 numbers is the heightened activation of the immune system. These findings were obtained both in the natural history of HIV infection and in primate models showing different disease courses. The mechanisms which lead to this hyperimmune activation are numerous and range from HIV specific effects including the persistent load of antigen, the cytokine storm resulting in increase sensitivity and priming to proapoptotic molecules. An alternative model has recently been proposed and suggests that the disruption of the mucosal barrier which can be attributed to the massive infection of the gut by HIV leads to the release of commensal bacterial products. These products will in turn activate the dendritic cells and other immune cells through the ligation of Toll like receptors leading potentially to the release of cytokines such as type I Interferons which in turn could upregulate the expression of TRAIL or other mediators of cell death. Ligation of TLRs could stem not only from commensal bacteria but also from HIV itself. Indeed HIV encompasses several GU rich sequences which can interact with TLR 7 and also activate dendritic cells to produce type I interferons. Ligation of TLR receptors on dendritic cells leads to the upregulation of PDL-1 and PDL-2, the ligands on APCs of the PD1 molecule. We and others have recently shown that PD1 is upregulated in cells from HIV infected persons as a result of chronic immune activation. It is hence more than likely that the interaction of PD-1 with its ligands initiated by the constant engagement of the T cell receptor with Ag concomitantly with and by the ligation of TLRs by HIV GU sequences could lead to the demise of the capacity of dendritic cells to induce the priming of naTve T cells and the induction of memory CD4 + T cells. We will determine whether aberrant interplay of CD4+ T cells and DC expressing PDL1 and PDL2 will lead to their functional and physical exhaustion. We will test the hypothesis that elevated levels of PD-1 on CD4+ T cells and PD-1 ligands on antigen presenting cells are due to the heightened immune activation observed in HIV infection caused by the continuous exposure of DCs to several TLR ligands . Indeed we will define the contributions of the interplay between the HIV-encoded TLR-7 ligand and other bacterial ligands and dendritic cells on the cellular immune response and in particular the survival and functionality of dendritic cell and priming and survival of CD4+ T cells. Altogether our experiments will provide a molecular framework to bridge aberrant DC function and T cell activation.
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