Doctor of Philosophy

dissertationThirty years after the isolation of HIV, despite significant advances in the understanding of the mechanisms of viral pathogenesis, a cure remains out of sight. Despite the effectiveness of combination antiretroviral therapy (ART) at preventing virus replication, a stable, transcriptionally silent viral reservoir within resting memory CD4+ T cells persists and hampers HIV elimination. The current thinking in the field is that a combination of a hypothetical drug that reactivates latent viruses, with current antiretroviral therapy, will be an effective approach toward viral eradication. Several vaccination regimens and pathogen infections have been shown to correlate with a transient increase in the levels of plasma RNA in HIV-1 infected patients even in the presence of ART. Hence, it is tempting to speculate that exposure to microbial products either by vaccination or infection may trigger reactivation of latent viruses. Pathogen infections are primarily sensed through pattern recognition receptors. Toll-like receptors, the most well investigated pattern recognition receptors, are important sentinels of innate host defense. These sensors recognize structural patterns from pathogens and induce an immune response through downstream signaling cascades that, among others, culminate in the activation of NF-kappaB and other transcription factors. Since the viral promoter contains two tandem NF-kappaB binding sites, it is possible to iv speculate that toll-like receptor signaling toward reactivation of latent HIV has recently gained impetus. In this dissertation, I review the emerging body of literature on the correlation between NF-kappaB signaling, as triggered by tolllike receptor engagement, and the reactivation of latent HIV-1. Second, I present our findings that Pam3CSK4, a toll-like receptor-1/2 agonist, can reactivate latent HIV in primary CD4+ T cells in vitro and in cells from aviremic patients. Finally, I described the ability of dynasore, a dynamin inhibitor, to activate latent HIV-1 provirus alone or in synergy with Pam3CSK4, and with well-known latencyreversing agents, such as SAHA, bryostatin-1 and JQ-1. HIV latency is a complex phenomenon controlled by different molecular mechanisms. Although several latency-reversing agents have been described in the literature, the efficacy of these agents to eliminate the transcriptionally silent reservoir in past clinical trials has been limited. Toll-like receptor signaling represents a novel tool in our armamentarium against latent HIV, and therefore deserves further exploration. Throughout the body of this work, I define two novel approaches that could provide us with new therapeutic interventions towards the eradication of the latent reservoir and a cure for HIV/AIDS