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Investigating the Ubiquitin-Proteasome System for Targeted Reversal of HIV-1 Latency

by
Timothy A. Russnak
BS - Rutgers University 2009

Thesis advisor: Joseph Dougherty, Ph.D.

Graduate Program in Microbiology & Molecular Genetics

RWJMS Research Tower
Room V10

Monday, October 16, 2017
2:00 p.m.


Abstract

HIV is a worldwide epidemic, remaining the ever-present specter among all matters regarding blood or other bodily fluids, such as sexual intercourse, healthcare, blood transfusions, or even surgery, particularly in resource-poor areas. While antiretroviral drug therapy is highly successful in suppressing the virus and preventing transmission, it cannot cure the infection due to latency Ė the ability of HIV to go into a silent state within cells; once drug therapy is stopped, reactivating latent virus will cause a surge of the viral load within days or weeks. Current drug therapies donít act on this latent reservoir, necessitating lifelong adherence to medication, which is both extremely costly and comes with negative side-effects. The mainstay of research into HIV latency deals with teasing apart the mechanisms involved in establishing and maintaining latency, in the hopes to find drug compounds which can efficiently reverse latency and thus purge the body of hidden HIV.
In searching for cellular pathways involved in latency, our lab has employed a genome-wide negative-selection screen, which indicated that the ubiquitin-proteasome system plays a role in maintaining latency. This led us to discover that proteasome inhibitors act as bifunctional antagonists of HIV, both reversing the latent state and reducing infectivity of virions. We then sought to determine what particular aspect of the ubiquitin-proteasome system was involved in maintaining latency, which we found to be ‚-catenin, a transcription factor which is marked for proteasomal degradation by the E3 ligase ‚-Trcp. This led us to investigate the activity of a small-molecule inhibitor of ‚-Trcp, showing its ability to reactivate latent HIV in both a primary cell model and in cells taken from aviremic HIV+ patients. These results are a proof-of-concept that inhibition of an E3 ligase can allow for specific reversal of HIV latency.


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