UCLA

Human immunodeficiency virus (HIV) remains a significant global health challenge, despite advancements in treatment. Antiretroviral therapy (ART) suppresses viral replication, but is not a cure. HIV persists in reservoirs of long-lived, memory CD4+ T cells harboring integrated, replication-competent provirus in a latent state. Viral persistence not only jeopardizes long-term health outcomes, but also complicates efforts to eradicate the virus, underscoring the need for innovative therapeutic approaches to achieve a cure.

One strategy known as the “kick and kill” approach aims to eliminate latently infected cells via pharmacological latency reversing agents (LRAs), which activate viral transcription, protein expression and virion production, thereby triggering these cells to be eliminated by viral-mediated cytolysis, immune detection or HIV-specific antiviral therapies. Despite some success in viral reactivation, existing LRAs failed to clear reactivated cells in vivo, emphasizing the urgent need for more effective treatments to promote the turnover of latently-infected cells.In collaboration with Paul Wender’s group at Stanford, our lab previously demonstrated that the latency-reversing capabilities and tolerability of naturally occurring protein kinase C (PKC) modulators, including bryostatin-1 and prostratin, can be improved by designing synthetic analogs of these compounds. SUW133, a potent bryostatin-1 analog, triggered latent HIV expression and led to the death of reactivated cells in humanized mice. However, whether this translates into clinically relevant outcomes remains unknown.

In this dissertation, I present a study evaluating the efficacy of PKC modulating HIV latency reversing agents, particularly SUW133, in the context of a “kick and kill” approach, as a novel therapeutic strategy against HIV persistence. Using a genetically barcoded HIV library in the context of a humanized mouse model, we quantified changes in the viral reservoir and found that SUW133 delayed viral rebound and reduced the number of unique barcoded viruses rebounding from the reservoir. Additionally, the combination of SUW133 plus NK cells further delayed rebound and reduced rebounding viral clones, even seemingly eliminating the viral reservoir in a subset of mice.

Next, we characterized the effects of SUW133 on NK cells to evaluate whether it modulates effector functions to enhance clearance of reactivated cells. While SUW133 induced changes in the activation profile of NK cells, it did not result in enhanced killing. Transcriptomic analysis revealed that CD4+ T cells had stronger responses to LRA than did NK cells, suggesting its effect on reservoir reduction is primarily due to augmenting the “kick” rather than “kill” arm of this therapeutic approach.

Lastly, I conclude with potential future directions, including some preliminary work evaluating synergistic combinations of SUW133 and histone deacetylase inhibitors (HDACi) as another novel therapeutic strategy towards latency reversal. Together, the work presented in this dissertation represents a multifaceted examination of the effects of SUW133 on latency reversal, highlighting new and exciting opportunities for its use towards an HIV cure.