Grant: Project Grant

More than 40 years after its discovery, HIV remains a global health challenge, with over 40 million people living with the virus (PWH). While antiretroviral therapy (ART) has significantly improved the quality of life for those affected, the persistent spread of the virus, combined with ongoing stigma, high treatment costs, and the emergence of drug resistance, underscores the urgent need for a safe, scalable, and efficient cure for HIV. ART does not cure HIV because of the presence of latent viral reservoirs. These reservoirs are long-lived and resistant to standard treatments, meaning that even lifelong ART will not eradicate the virus. Recently, we identified a critical vulnerability in the persistent viral genome: HIV genomes containing a specific region, known as "psi", are preferentially depleted over time during ART. This suggests that the immune system exerts selective pressure on this small portion of the HIV genome. We hypothesize that the selective depletion of cells harboring genomes with an intact psi region is mediated by innate sensing mechanisms, a cell-intrinsic line of defense that leads to the death of the infected cell. We further hypothesize that this mechanism can be leveraged to eliminate HIV reservoirs. To test this hypothesis, we will characterize the psi region in HIV reservoirs by analyzing blood and tissues samples from PWH on ART. We will investigate which cells and tissues harbor intact VS mutated psi and explore how innate immune pressure contributes to the natural reduction of the viral reservoir. In addition, we will use molecular biology techniques to pinpoint the immune pathways that drive the elimination of latently infected cells. Finally, we will test drug combinations that enhance innate immune responses and induce HIV production and measure the efficacy of this strategy at depleting HIV reservoir cells. Together, these studies will provide critical insights into innovative strategies to target and ultimately eradicate HIV.