Andrew Badley

Equity Interest - Non-publicly traded entity ( e.g., stock, stock option, or other ownership interest)

Evaluating the role of the novel apoptosis inhibitor TRAILshort, in maintaining HIV persistence.

Recently, there has been great interest in developing novel strategies designed to cure HIV infection, using innovative strategies to inhibit HIV replication, o purge HIV from the cells within which it hides, and/or the augment the immune response to HIV, such that the host immune system can eradicate HIV infected cells. The research strategy employed in the current proposal is predicated upon a unique discovery made by our lab, wherein we have identified a new molecule produced by HIV infected cells which functions to antagonize the normal immune response to HIV. This protein that we call TRAILshort is produced by HIV infected cells, and it prevents HIV infected cells from dying after they come in contact with the cytotoxic molecule TRAIL, which is normally produced by CD8 T cells and NK cells of the immune system. TRAIL plays a critical role in eliminating malignant or virally infecte cells. It is therefore not surprising that TRAIL is upregulated in cells from HIV infected patients reflecting an immunologic response designed to eradicate HIV infected cells. However, it is clear that endogenous TRAIL alone is insufficient to kill HIV infected cells. Over the past decade, we have shown that (i) ex vivo administration of additional TRAIL is sufficient to eradicate HIV from HIV infected patients T cells (ii) that such TRAIL treatment does not cause quantitative or qualitative impairments in bystander T cell, B cell, or NK cell function and (iii) hat HIV infected patient PBMC produce TRAILshort which antagonizes normal TRAIL signaling. Now we have discovered that inhibiting TRAILshort allows the TRAIL which is already present to kill the HIV infected cells. Indeed, inhibiting TRAILshort with genetic approaches reduces HIV replication by ~ 3.5logs and reduces the number of cells which contain HIV provirus. In the current proposed research, we propose to develop ways of inhibiting TRAILshort in HIV infected patients and test these strategies impact on the selectively killing cells which contain HIV, ( while sparing cells which do not contain HIV), and evaluate how many HIV containing cells persist after TRAILshort inhibition. Ultimately these interventions will increase our understanding into novel approaches designed to cure HIV infection.