HIV-1 Latency as a Consequence of Chromatin Regulation

HIV-1 Latency as a Consequence of Chromatin Regulation

Bibliographic Details
Main Author: Friedman, Julia H.
Language:English
Published: Case Western Reserve University School of Graduate Studies / OhioLINK 2011
Subjects:
Molecular Biology
Virology
HIV-1
Latency
Epigenetics
Transcription
Heterochromatin
EZH2
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=case1301495389
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-case13014953892021-08-03T05:34:10Z HIV-1 Latency as a Consequence of Chromatin Regulation Friedman, Julia H. Molecular Biology Virology HIV-1 Latency Epigenetics Transcription Heterochromatin EZH2 HIV-1 Latency as a Consequence of Chromatin RegulationAbstractByJULIA H. FRIEDMAN HIV-1 is one of the most devastating diseases to have emerged in the past century. We can treat HIV+ patients with combined antiretroviral therapy (HAART) that essentially restricts viral replication to below limits of detection using clinical assays and prolongs the lifespan of those infected. However, these patients must remain on therapy for the duration of their lives, as going off HAART results in rebound of viral replication and subsequent CD4+ T cell depletion. The rebounding virus is produced from latently infected cells. These latent cells are memory CD4+ T cells that, due to their quiescent state, are restrictive for productive viral replication. Although there are many differences that can account for latency in these quiescent cells, such as a lack of nuclear localization of transcriptional initiation and elongation factors, one possible contribution is the establishment of heterochromatin around the integrated provirus. In this thesis, we have attempted to determine the consequences of integration into the human chromosome; specifically, the regulation of chromatin and its effects on HIV latency. We have corroborated the finding that nucleosome remodeling is an important step in the processive transcription of the HIV genome. Based on this and other evidence suggesting that HIV transcription can be epigenetically regulated, we wanted to identify other cellular factors involved in this process. We began by screening other heterochromatin associated proteins in a small scale shRNA approach. In this manner, we found that latently infected cells that were superinfected with EZH2 shRNA would spontaneously reactivate. EZH2 is a histone methyltransferase that can trimethylate lysine 27 on histone H3 (M3K27). This epigenetic mark has been implicated in other epigenetic regulated processes such as X-inactivation and Hox gene silencing. It appears, from chromatin immunoprecipation assays, that EZH2 is also resident along the promoter region of HIV proviruses. Treating latent cells with a drug that can specifically inhibit the M3K27 modification, DZNep, results in activation of latent viruses. As such, our findings have implicated a novel route for reactivation of latent proviruses. Understanding the molecular mechanisms underlying viral transcriptional silencing is paramount in the development of a novel therapeutic approach in the treatment of HIV. 2011 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1301495389 http://rave.ohiolink.edu/etdc/view?acc_num=case1301495389 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Molecular Biology
Virology
HIV-1
Latency
Epigenetics
Transcription
Heterochromatin
EZH2
spellingShingle Molecular Biology
Virology
HIV-1
Latency
Epigenetics
Transcription
Heterochromatin
EZH2
Friedman, Julia H.
HIV-1 Latency as a Consequence of Chromatin Regulation
author Friedman, Julia H.
author_facet Friedman, Julia H.
author_sort Friedman, Julia H.
title HIV-1 Latency as a Consequence of Chromatin Regulation
title_short HIV-1 Latency as a Consequence of Chromatin Regulation
title_full HIV-1 Latency as a Consequence of Chromatin Regulation
title_fullStr HIV-1 Latency as a Consequence of Chromatin Regulation
title_full_unstemmed HIV-1 Latency as a Consequence of Chromatin Regulation
title_sort hiv-1 latency as a consequence of chromatin regulation
publisher Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate 2011
url http://rave.ohiolink.edu/etdc/view?acc_num=case1301495389
work_keys_str_mv AT friedmanjuliah hiv1latencyasaconsequenceofchromatinregulation
_version_ 1719421826847735808

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