MEASUREMENT AND DISRUPTION OF HIV LATENCY IN CURE STRATEGIES

HIV infection is responsible for major morbidity, mortality, and cost to healthcare systems worldwide. While antiretroviral therapy (ART) provides a potent reduction of viremia and improvement in immune function, lifelong adherence is required to prevent viral rebound from the viral reservoir of latent, but replication competent proviral HIV DNA found mostly in the genomes of host CD4 T lymphocytes. Significantly, a lifetime of treatment is associated with financial burden, incomplete immune recovery, and stigma. Thus, a cure for HIV is of substantial public health interest. However, a cure for HIV remains elusive due to the viral reservoir. A central strategy for cure is the use of latency reversal agents (LRAs) to induce proviral expression in conjunction with an immunotherapy in order to augment immune clearance of virally infected cells.Assessment of HIV cure intervention/therapeutic efficacy requires careful characterization and measurement of the viral reservoir. Importantly, the vast majority of proviruses within the viral reservoir contain defects that render them replication-incompetent. Herein, the evaluation and implementation of novel, state-of-the-art digital PCR and near-full-length sequencing methodologies to selectively measure intact proviruses in HIV cure clinical trials is described. In addition, implementation of cure strategies will require knowledge of the factors regulating the HIV reservoir across all human populations. Despite this, a major limitation of cure trials to date is limited enrollment of women and poor understanding of the impact of biological sex on the HIV reservoir. This work provides one of the first exhaustive assessments of the impact of biological sex on the HIV reservoir and on immune activation parameters. Finally, latency reversal strategies to date have been limited by dose-limiting toxicities of LRAs and insufficient latency reversal from non-toxic agents. A safe and effective strategy to reverse latency that builds upon these early attempts to reverse latency is needed. Here, a novel, targeted strategy to strongly reverse HIV latency through non-canonical Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB) agonism is described. In addition, novel synergistic combinations of latency reversal agents that may be leveraged to increase latency reversal efficacy are identified.Doctor of Philosoph