TARGETING THE CLASS I HDACS TO DISRUPT QUIESCENT HIV-1 PROVIRUSES Public Deposited

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  • March 20, 2019
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  • Barton, Kirston Mandy Lang
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Infection with the human immunodeficiency virus type 1 (HIV-1) was first described in a report in the Morbidity and Mortality Weekly Report in June of 1981. Since that time millions of people around that world have been affected by HIV-1 infection. In the last three decades, significant advances have been made in the treatment of people who are infected with HIV-1. However, there is still no cure for HIV-1 infection. The primary obstacle to viral clearance is the existence of long-lived cells harboring replication competent quiescent proviruses. One approach that has been proposed for elimination of this replication competent virus from infected patients is called the induce and clear method. This dissertation focuses on identifying factors that could potentially be used as therapeutic targets for induction of quiescent HIV-1 proviruses. c-Myc and YY1 are two well-known transcription factors that have been demonstrated to bind to the HIV-1 long terminal repeat (LTR) and recruit repressive histone deacetylase (HDAC) enzymes. Therefore, the hypothesis was that specifically targeting factors that recruit HDAC to the HIV-1 promoter would be sufficient to disrupt occupancy of the HDACs and induce expression from quiescent proviruses. The results demonstrate that depletion of YY1 is sufficient to induce expression from quiescent proviruses in two models of HIV-1 latency; however, it did not affect the residence of HDACs at the HIV-1 LTR. To further identify specific targets for disruption of quiescent HIV-1, the next step was to elucidate which of the class I HDACs was important for the strong induction of transcription from HIV-1 promoters following treatment with class I selective HDAC inhibitors. Individual depletion of HDAC1, -2, and -3 demonstrated that depletion of HDAC1 and HDAC2 does not affect transcription from the HIV-1 promoter; however, depletion of HDAC3 does significantly induce transcription from quiescent HIV-1 promoters, indicating that it may be possible to reverse latency using therapeutics targeting HDAC3. The overall conclusions of this thesis indicate that redundant mechanisms of HDAC recruitment are present at HIV-1 LTRs and therefore depletion of HDAC recruiters may not be sufficient to disrupt latency. However, HDAC3 is a potential therapeutic target for induction of transcription from the HIV-1 promoter.
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  • In Copyright
Advisor
  • Margolis, David
Degree
  • Doctor of Philosophy
Graduation year
  • 2013
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