Grant: Fellowship - Priority Announcement - HIV/AIDS and/or STBBI

Antiretroviral therapy (ART) suppresses HIV replication to undetectable levels. However, the persistence of latent viral reservoirs (VR) consisting majorly of CD4+ T cells and to some extent, macrophages allows for a rebound of viremia upon ART treatment interruption. Some of the most effective agents currently used in HIV treatment can reactivate cells that are latently infected with HIV by activating canonical/classical NF-kB pathway. But, these compounds are unable to clear out the reactivated cells and the effect is often associated with increased inflammation. Consequently, there is a need for novel therapeutics to eliminate/reduce the latent VR to achieve a stable remission of HIV. Cells that are latently infected with HIV are maintained in part by increased expression of inhibitors of apoptosis proteins, IAPs, these proteins are responsible for blocking caspase activities leading to prolonged cell survival. Second mitochondrial activator of caspases (SMAC) were shown to compromise cell survival by degrading IAPs. They further hijack host machinery and activate the non-canonical NF-kB pathway. This leads to the induction of cell death by activation of caspases. In this context, the current study is designed to investigate the effect of DIABLO/SMAC mimetic (SM) and particularly APG-1387, a novel SM developed primarily for cancer application as HIV latency reversing agent and to elucidate its mode of action and effect on viral reservoirs.