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EPIGENETIC REGULATION OF HIV-1 LATENCY BY HISTONE H3 METHYLTRANSFERASES AND H3K27 DEMETHYLASE

Nguyen, Kien
http://rave.ohiolink.edu/etdc/view?acc_num=case1491495889537421

Abstract Details

2017, Doctor of Philosophy, Case Western Reserve University, Molecular Biology and Microbiology.
HIV-1 infection remains a challenging infectious disease. Although highly active antiretroviral therapy (HAART) is effective in suppressing viral replication below detectable levels, it fails to eradicate HIV-1. Interruption of HAART results in reactivation of HIV-1 replication from latent proviruses which mainly reside in CD4+ resting memory T cells. Latent HIV-1 is very stable in the body even under HAART and considered the last barrier for HIV-1 cure. Current efforts seek to understand mechanisms underlying the formation of latent HIV-1 reservoirs and develop drugs capable of reactivating latent proviruses. We demonstrate a critical role for the Polycomb repressive complex 2 (PRC2), the histone H3 lysine 27 methyltransferase complex, for the maintenance of HIV-1 latency in Jurkat T cells. Both depletion and knockout of EZH2, a catalytic subunit of PRC2, spontaneously induce latent proviruses and strongly sensitize them for exogenous stimuli. However, knockout of G9a, a histone H3 lysine 9 methyltransferase, fails to reactivate latent HIV-1 in this system. By contrast, depletion of EZH2 and G9a in Jurkat T cells prior to HIV-1 infection significantly reduce levels of the resulting silenced viruses. In contrast to the Jurkat T cells, inhibition of EZH2 (by GSK-343 or EPZ-6438) and G9a (by UNC-0638) in resting memory T cells cultured ex vivo or isolated from infected patients receiving HAART caused moderate reactivation of latent proviruses. We conclude that both PRC2 and G9a are required for the establishment and maintenance of HIV-1 latency in T cells. EZH2 inhibitors (GSK-343 and EPZ-6438), or the G9a inhibitor UNC-0638 are potential candidates for use as latency-reversing agents in clinical studies. In addition, the role of H3K27 demethylase UTX1 as an inhibitor of HIV-1 latency in T cells is also characterized. Compared to latent proviruses, UTX1 is more enriched at the promoter of reactivated HIV-1. Its depletion restricts the reactivation of latent HIV-1 in both Jurkat T cells and resting primary T cells. Inhibition of UTX1 by GSKJ4 not only promotes HIV-1 silencing but also prevents reactivation of latent HIV-1 in primary T cells. The rise of HIV-1 DNA methylation resulting from UTX1 depletion increases latent HIV-1 resistance to reactivation.
Jonathan Karn, PhD (Advisor)
Jacek Skowronski, PhD (Committee Chair)
Paul Macdonald, PhD (Committee Member)
David McDonald, PhD (Committee Member)
153 p.
Molecular Biology; Virology
HIV-1 latency, PRC2, G9a, UTX1, epigenetic

Recommended Citations

Citations

  • Nguyen, K. (2017). EPIGENETIC REGULATION OF HIV-1 LATENCY BY HISTONE H3 METHYLTRANSFERASES AND H3K27 DEMETHYLASE [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1491495889537421

    APA Style (7th edition)

  • Nguyen, Kien. EPIGENETIC REGULATION OF HIV-1 LATENCY BY HISTONE H3 METHYLTRANSFERASES AND H3K27 DEMETHYLASE . 2017. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1491495889537421.

    MLA Style (8th edition)

  • Nguyen, Kien. "EPIGENETIC REGULATION OF HIV-1 LATENCY BY HISTONE H3 METHYLTRANSFERASES AND H3K27 DEMETHYLASE ." Doctoral dissertation, Case Western Reserve University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1491495889537421

    Chicago Manual of Style (17th edition)

case1491495889537421
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© 2017, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.