It is well accepted that HIV infection causes an accelerated rate of CD4 T cell apoptosis that contributes to the CD4 T cell losses which occur in an HIV infected patient. It is also well accepted that HIV gp120 can trigger a variety of cell type including CD4 T cells to undergo apoptosis, using signaling pathways that involve P38, JNK, Caspases, and mitochondrial depolarization. Finally it is well accepted that other mechanisms contribute to CD4 T cell loss during HIV disease, including enhanced production of proapoptotic ligands (FasL and TRAIL) by HIV infected macrophages and dendritic cells, microbial translocation across the gut epithelia, and cytotoxic effects of other HIV proteins including Tat, Nef, and Vpr. What remains unknown is whether there is a common mechanism which ties these distinct pathways together. We will present preliminary data in primary CD4 T cells suggest a novel underlying mechanism which links each of these pathways, whereby X4 gp120 signaling through CXCR4 first causes an apoptosis prone phenotype of CD4 T cells by altering the regulation of microRNA, such that Foxo3A is upregulated, and together with JNK (also activated by gp120), Foxo3A is activated, resulting in enhanced transcription of apoptotic regulatory molecules including BIM. This then allows gp120 primed and apoptosis prone cells to undergo apoptosis when they encounter proapoptotic stimuli whether that be FasL, Tat, or more gp120. Of special interest, gp120 stimulation also has the effect of priming CD4 T cells to die following exposure to the bacterial product, LPS by virtue of upregulating the Toll like receptor machinery. Given the pervasive nature of gp120 and its diverse effects on the immune regulation of HIV infected patients, it is of great interest to examine the immune effects of effective CXCR4 inhibition; consequently we will carefully examine both the immune and antiviral effects of a new class of CXCR4 inhibitor which is in clinical development, KRH-1636. Results of the proposed investigations will both inform and increase the understanding of the immunopathogenesis of HIV; how the microbial translocation hypothesis directly causes CD4 T cell loss and the clinical efforts to develop a CXCR4 inhibitor that is free of off-target effects.
The development of AIDS, as a consequence of infection with the human immunodeficiency virus (HIV), is associated with profound immunodeficiency, secondary to the depletion of CD4 T cells. Considerable evidence indicates that the mode of CD4 T cell loss is through aberrant induction of cell death, and a variety of mechanisms have been proposed to initiate this death. It is apparent now that there is an underlying predisposition of these CD4 T cells to undergo death in response to a variety of different triggers. The underlying goal of this grant is to understand how HIV causes the CD4 T cells to become predisposed to cell death. Preliminary data presented in the current proposal support the hypothesis that HIV gp120 alters a normal host gene control mechanism of called microRNA, which determine in part how much of a protein is produced within a cell. By interfering with that regulatory step, gp120 impacts the expression of proteins which control apoptosis signaling. Therefore when a cell which has altered microRNA expression encounters, for example, bacterial products in the circulation, that cell is now able to signal the cell to commit suicide. y completely understanding the reason that cells die during HIV infection, novel approaches to augmenting the immune system can be developed for the treatment of persons infected with HIV.
