ANALYZING HIV-1 CURE STRATEGIES AND RESERVOIR QUANTIFICATION METHODS

Abstract

Although antiretroviral therapy (ART) can effectively prevent HIV-1 replication in infected hosts, the maintenance of a stable reservoir of proviral DNA, localized mostly to resting CD4+ T cells, prevents complete eradication of the virus. As a result, numerous researchers have attempted to design an effective and safe cure strategy to either eradicate the HIV-1 reservoir (a “sterilizing” cure) or achieve virologic control in the absence of ART (a “functional” cure). Two of the most prominent strategies that have emerged are the “shock and kill” and “block and lock” strategies, which aim to achieve a sterilizing and functional cure, respectively. Regardless of the approach, achieving a viable cure strategy will require a consensus on how best to identify and quantify the composition and size of the viral reservoir, a consensus which has not yet been reached. In this thesis, I first present an overview of the diverse composition and behaviors of HIV-1 reservoirs, as CD4+ T cells only represent a portion of the total reservoir. This then informs my analysis of the utility, relevance, and implications of numerous HIV-1 assays as they relate to the aforementioned cure strategies. Subsequently, I assess the efficacy of established and developing “shock and kill” and “block and lock” cure approaches, with the goal of determining the most plausible and reasonable next steps for HIV1 cure research. I propose a more comprehensive, multi-faceted, and standardized approach to reservoir quantification, which I claim is essential to accurately measuring the efficacy of HIV-1 cure strategies in clinical studies. I also find that the “block and lock” strategy is a more feasible approach to an HIV-1 cure compared to the “shock and kill” strategy, though the current data demonstrate a need for further refinement of the approach. Taken together, my thesis further emphasizes the need for a more thorough understanding of HIV-1 reservoir dynamics and for more effective assays in order to achieve a cure.