Ever since their existence, there has been an everlasting arms race between viruses and their host cells. Host cells have developed numerous strategies to silence viral gene expression, whereas viruses always find ways to overcome these obstacles. Accordingly, viruses have evolved to take full advantage of existing cellular chromatin components to activate or repress its own genes when needed. In fact, host epigenetic modifications of the herpesviral genome chromatin play a key role in the transcriptional control of latent and lytic genes during a productive viral lifecycle. Kaposi's sarcoma-associated herpesvirus (KSHV) is a ubiquitous herpesvirus that establishes a life-long persistent infection in humans and is associated with Kaposi's sarcoma and several lymphoid malignancies. During latency, the KSHV genome persists as a multicopy circular DNA assembled into nucleosomal structures. While viral latency is characterized by restricted viral gene expression, reactivation induces the lytic replication program and the expression of viral genes in a defined sequential and temporal order. Our preliminary study demonstrates that (1) the latent and lytic chromatins of KSHV are associated with a distinctive pattern of activating and repressive histone modifications whose distribution changes upon reactivation in an organized manner in correlation with the temporally ordered expression of viral lytic genes. Furthermore, (2) the evolutionarily conserved Polycomb group proteins and histone deubiquitinases also play a critical role in the regulation of KSHV latency and reactivation by regulating the viral chromatin structure. Thus, the epigenetic program of KSHV is at the crux of restricting latent gene expression and the orderly expression of lytic genes. The goal of this study is to better understand how epigenetic modifications of the KSHV genome affect viral latency and lytic replication, to thereby contribute to the development of a persistent infection and subsequent pathogenic events in vivo. Based on our preliminary studies, we hypothesize that the proper epigenetic regulation of the KSHV genome is critical for viral persistency during latency and reactivation, and for pathogenesis in KSHV infected lesions. This proposal is highly innovative, utilizing well-established comprehensive genome-wide ChIP array, BAC genetics, and in vivo experimental conditions.

Public Health Relevance

Kaposi sarcoma (KS) is the leading cause of cancer in patients with HIV infection. While there is a reduction in the incidence of KS among patients receiving HAART, an increasing concern is the development and spread of drug resistant HIV-1 strains, which in turn leads to reoccurrence of KS complication. Kaposi's sarcoma-associated herpesvirus (KSHV) is an etiological agent to induce KS tumors, pleural effusion lymphomas and multicentric Castleman's disease. We have recently developed a new primate model that significantly recapitulates the important aspects of the KSHV infection and pathogenesis of humans, thus providing a unique tool for understanding KSHV infection. The goal of this study is to better understand how epigenetic modifications of the KSHV genome affect viral latency and lytic replication, to thereby contribute to the development of a persistent infection and subsequent pathogenic events in vivo. The proposed study is highly innovative by utilizing the well-established in vitro and in vivo experimental conditions and a successful outcome should be a major discovery that significantly impacts the understanding of KSHV persistent and pathogenic infection.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115284-08
Application #
8460154
Study Section
Special Emphasis Panel (ZRG1-AARR-K (03))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2005-06-01
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$281,656
Indirect Cost
$107,794
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Lee, Hye-Ra; Mitra, Jaba; Lee, Stacy et al. (2016) Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Perturbs the G1-S Cell Cycle Progression via Deregulation of the cyclin D1 Gene. J Virol 90:1139-43
Lee, Myung-Shin; Yuan, Hongfeng; Jeon, Hyungtaek et al. (2016) Human Mesenchymal Stem Cells of Diverse Origins Support Persistent Infection with Kaposi's Sarcoma-Associated Herpesvirus and Manifest Distinct Angiogenic, Invasive, and Transforming Phenotypes. MBio 7:e02109-15
Bowman, James; Rodgers, Mary A; Shi, Mude et al. (2015) Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation. MBio 6:e01777-15
Brulois, Kevin; Wong, Lai-Yee; Lee, Hye-Ra et al. (2015) Association of Kaposi's Sarcoma-Associated Herpesvirus ORF31 with ORF34 and ORF24 Is Critical for Late Gene Expression. J Virol 89:6148-54
Cheng, Fan; Sawant, Tanvee Vinod; Lan, Ke et al. (2015) Screening of the Human Kinome Identifies MSK1/2-CREB1 as an Essential Pathway Mediating Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication during Primary Infection. J Virol 89:9262-80
Liang, Chengyu; Oh, Byung-Ha; Jung, Jae U (2015) Novel functions of viral anti-apoptotic factors. Nat Rev Microbiol 13:7-12
Liang, Qiming; Chang, Brian; Lee, Patrick et al. (2015) Identification of the Essential Role of Viral Bcl-2 for Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication. J Virol 89:5308-17
Lee, Hye-Ra; Amatya, Rina; Jung, Jae U (2015) Multi-step regulation of innate immune signaling by Kaposi's sarcoma-associated herpesvirus. Virus Res 209:39-44
Jung, Jae; Münz, Christian (2015) Immune control of oncogenic γ-herpesviruses. Curr Opin Virol 14:79-86
Seo, Gil Ju; Yang, Aerin; Tan, Brandon et al. (2015) Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway. Cell Rep 13:440-9

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