A number of mechanisms have been put forward to explain the depletion of CD4 cells including cytopathiceffect of the virus, reduced de novo production of T cells and killing of virally infected cells by HIV specificCD8+ T cells. Recently several groups have provided evidence indicating that the best correlate of thedecrease in CD4 numbers is the heightened activation of the immune system. These findings were obtainedboth in the natural history of HIV infection and in primate models showing different disease courses. Themechanisms which lead to this hyperimmune activation are numerous and range from HIV specific effectsincluding the persistent load of antigen, the cytokine storm resulting in increase sensitivity and priming toproapoptotic molecules. An alternative model has recently been proposed and suggests that the disruption ofthe mucosal barrier which can be attributed to the massive infection of the gut by HIV leads to the release ofcommensal bacterial products. These products will in turn activate the dendritic cells and other immune cellsthrough the ligation of Toll like receptors leading potentially to the release of cytokines such as type IInterferons which in turn could upregulate the expression of TRAIL or other mediators of cell death. Ligationof TLRs could stem not only from commensal bacteria but also from HIV itself. Indeed HIV encompassesseveral GU rich sequences which can interact with TLR 7 and also activate dendritic cells to produce type Iinterferons. Ligation of TLR receptors on dendritic cells leads to the upregulation of PDL-1 and PDL-2, theligands on APCs of the PD1 molecule. We and others have recently shown that PD1 is upregulated in cellsfrom HIV infected persons as a result of chronic immune activation. It is hence more than likely that theinteraction of PD-1 with its ligands initiated by the constant engagement of the T cell receptor with Agconcomitantly with and by the ligation of TLRs by HIV GU sequences could lead to the demise of thecapacity 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 totheir functional and physical exhaustion. We will test the hypothesis that elevated levels of PD-1 on CD4+ Tcells and PD-1 ligands on antigen presenting cells are due to the heightened immune activation observed inHIV infection caused by the continuous exposure of DCs to several TLR ligands . Indeed we will define thecontributions of the interplay between the HIV-encoded TLR-7 ligand and other bacterial ligands anddendritic cells on the cellular immune response and in particular the survival and functionality of dendritic celland priming and survival of CD4+ T cells. Altogether our experiments will provide a molecular framework tobridge aberrant DC function and T cell activation.
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