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.
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.
|Brulois, Kevin; Jung, Jae U (2014) Interplay between Kaposi's sarcoma-associated herpesvirus and the innate immune system. Cytokine Growth Factor Rev 25:597-609|
|Kronstad, Lisa M; Brulois, Kevin F; Jung, Jae U et al. (2014) Reinitiation after translation of two upstream open reading frames (ORF) governs expression of the ORF35-37 Kaposi's sarcoma-associated herpesvirus polycistronic mRNA. J Virol 88:6512-8|
|Lee, Myung-Shin; Jones, Tiffany; Song, Dae-Yong et al. (2014) Exploitation of the complement system by oncogenic Kaposi's sarcoma-associated herpesvirus for cell survival and persistent infection. PLoS Pathog 10:e1004412|
|Full, Florian; Jungnickl, Doris; Reuter, Nina et al. (2014) Kaposi's sarcoma associated herpesvirus tegument protein ORF75 is essential for viral lytic replication and plays a critical role in the antagonization of ND10-instituted intrinsic immunity. PLoS Pathog 10:e1003863|
|Liang, Qiming; Seo, Gil Ju; Choi, Youn Jung et al. (2014) Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe 15:228-38|
|Bai, Zhiqiang; Huang, Yufei; Li, Wan et al. (2014) Genomewide mapping and screening of Kaposi's sarcoma-associated herpesvirus (KSHV) 3' untranslated regions identify bicistronic and polycistronic viral transcripts as frequent targets of KSHV microRNAs. J Virol 88:377-92|
|Lee, Hye-Ra; Doganay, Sultan; Chung, Brian et al. (2014) Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 4 (vIRF4) targets expression of cellular IRF4 and the Myc gene to facilitate lytic replication. J Virol 88:2183-94|
|He, Zhiheng; Zhao, Jun; Zhang, Junjie et al. (2014) NF-?B activation coordinated by IKK? and IKK? enables latent infection of Kaposi's sarcoma-associated herpesvirus. J Virol 88:444-55|
|Rodgers, Mary A; Bowman, James W; Fujita, Hiroaki et al. (2014) The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J Exp Med 211:1333-47|
|Rodgers, Mary A; Bowman, James W; Liang, Qiming et al. (2014) Regulation where autophagy intersects the inflammasome. Antioxid Redox Signal 20:495-506|
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