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Leia Kaye Miller
B.S., East Tennessee State University 2005
Thesis Advisor: Joseph P. Dougherty, Ph.D.
Graduate Program in Microbiology & Molecular Genetics
RWJMS Research Tower, Room V-10
Monday, November 25, 2013
It is estimated that over 30 million people worldwide are infected with human immunodeficiency virus type 1 (HIV-1). Although the advent of highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality associated with HIV-1 infection, it cannot cure the infection. Therefore, patients must remain on HAART for life. The fact that HIV-1 can establish a latent infection in long-lived cell types largely accounts for its persistence in patients on HAART. A potential strategy to eliminate the latent reservoir of HIV-1 involves the administration of drugs that are capable of activating latent virus such that it becomes susceptible to the host immune system and/or to HAART. Therefore, it was our goal to identify novel cellular regulators of HIV-1 latency to lay the foundation for strategies to mediate viral clearance.
We employed a genome-wide RNA interference screen to identify genes involved in the maintenance of HIV-1 latency. The results from our screen indicated a novel role for the ubiquitin-proteasome system in the regulation of HIV-1 latency. We were able to demonstrate that proteasome inhibitors (PIs) are potent activators of latent HIV-1 transcription, viral gene expression, and virion production in several in vitro model systems including primary CD4+ T cell models. Therefore, our results categorize PIs as a new class of HIV-1 latency antagonists. Mechanistically, we found that PIs activate latent HIV-1, at least in part, through the stabilization of the transcription factor ƒÒ-catenin. Additionally, we confirmed that PIs exhibit a second anti-HIV-1 function in their ability to inhibit HIV-1 replication. As such, we were able to show that PIs act as bifunctional antagonists of both HIV-1 latency and replication. Therefore, our findings demonstrate the feasibility of developing effective dual-acting inhibitors of HIV-1. This is a novel concept that can be applied to the development of pioneering anti-HIV-1 pharmaceuticals with the potential to substantially impact the goal of purging HIV-1 from infected individuals.