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Novel Mechanisms of Maintaining and Abrogating HIV-1 Latency

by
Bradley D. Phelan
BS, 2000
University of Wisconsin-Madison

Thesis Advisor: Joseph Dougherty, PhD

Graduate Program in Molecular Genetics, Microbiology & Immunology

11:30 am
CABM Room 010

Thursday, August 20, 2009
11:30 am


Abstract

Human Immunodeficiency Virus Type 1 (HIV-1) is a complex lentivirus capable of infecting a variety of human cells, with tropism for those in the immune system. HIV infection of CD4+ cells causes a serious depletion of T cell subsets and results in Acquired Immune Deficiency Syndrome (AIDS) and death arising from complications caused by associated opportunistic infections.

It was realized that HIV could linger because of an infected subpopulation of extremely long-lived CD4+ T cells. The capacity for becoming phenotypically latent in cells which could survive for several years had many repercussions: the virus could escape drug therapies, could not be neutralized by antibodies or immune cells, and could not be cleared.

Even in patients successfully treating their condition, low levels of viral replication are present. Genetic analysis of these virions reveals that the residual virus originates from the pool of near dormant infected cells, indicating that little to no exhaustion of the latent reservoir is occurring.

HIV latency is the lack of sustaining the expression of HIVís positive feedback regulation circuit, resulting in a non-productive state. This dormant state is reversible and occurs readily in T cells upon stimulation.

This demonstrates the need and possibility for reservoir-purging therapy. Directed approaches to specifically target the reactivation of latent proviruses are being developed. It is apparent that several mechanisms are responsible for maintaining viral latency. Thus, the development of multiple therapeutic treatments which utilize diverse mechanisms will likely be required for cleansing the bodyís reservoirs of residual virus. In this work, we report compounds with the capacity to reactive HIV from latently infected cells. Several of these compounds function by previously unreported mechanisms and/ or already have attained FDA approval.


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