Kaposi's sarcoma-associated herpesvirus (KSHV) is a ubiquitous virus that establishes a life-long persistent infection in humans and is associated with Kaposi's sarcoma and several lymphoid malignancies. It has now become clear-following epidemiological, serological, and virological studies-that KSHV legitimately joins the ranks of EBV, CMV, and HHV-6 and-7 as a true oral herpesvirus. 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. (2) It is intriguing to observe the unique epigenetic profiles of KSHV genome in oral epithelial cells where the KSHV genome primarily undergoes transcriptionally active euchromatin formation, leading to spontaneous lytic replication. (3) We have developed an """"""""infectious"""""""" KSHV bacterial artificial chromosome (BAC16) and NOD/SCID IL2Rg-/- (NSG) """"""""humanized"""""""" mouse model that allows efficient viral genetic manipulation and in vivo persistence study, respectively. Based on our preliminary studies, we hypothesize that the differential epigenetic modification of the KSHV genome is the crux of determining latent infection vs. lytic reactivation of in vivo viral lifecycle. We will investigate the transition mechanism between euchromatin and heterochromatin during de novo infection of various cells including oral epithelial cells, and utilize small molecule inhibitors, gene knockdown and mutants to alter the epigenetic modifications for KSHV lytic gene expression cascade and latency (Aim 1). Subsequently, we will define in vivo roles of the epigenetic modifications of the KSHV genome for viral persistence by utilizing NSG """"""""humanized"""""""" mouse model (Aim 2). Thus, this study will show that histone-modifying enzymes involved in the regulation viral gene expression ultimately serves as pharmaceutical targets to control KSHV-associated oral complications.

Public Health Relevance

It has become clear-following epidemiological, serological, and virological studies-that KSHV legitimately is a true oral herpesvirus. However, we are far from understanding the molecular details of oral complications associated with KSHV due to the lack of functional genetic system and animal model for KSHV. Thus, it is important to develop physiologically relevant experimental systems to understand KSHV epigenome as well as to facilitate the development of new strategies for KSHV-associated oral complication.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Schools of Medicine
Los Angeles
United States
Zip Code
Liang, Qiming; Wei, Dahai; Chung, Brian et al. (2018) Novel Role of vBcl2 in the Virion Assembly of Kaposi's Sarcoma-Associated Herpesvirus. J Virol 92:
Foo, Suan-Sin; Chen, Weiqiang; Chan, Yen et al. (2018) Biomarkers and immunoprofiles associated with fetal abnormalities of ZIKV-positive pregnancies. JCI Insight 3:
Gruffaz, Marion; Zhou, Shenghua; Vasan, Karthik et al. (2018) Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi's Sarcoma-Associated Herpesvirus Latent and Lytic Replications. MBio 9:
Foo, Suan-Sin; Chen, Weiqiang; Chan, Yen et al. (2017) Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy. Nat Microbiol 2:1558-1570
Hwang, Sung-Woo; Kim, DongIk; Jung, Jae U et al. (2017) KSHV-encoded viral interferon regulatory factor 4 (vIRF4) interacts with IRF7 and inhibits interferon alpha production. Biochem Biophys Res Commun 486:700-705
Cheng, Fan; He, Meilan; Jung, Jae U et al. (2016) Suppression of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by 5'-AMP-Activated Protein Kinase. J Virol 90:6515-6525
Zhu, Ying; Ramos da Silva, Suzane; He, Meilan et al. (2016) An Oncogenic Virus Promotes Cell Survival and Cellular Transformation by Suppressing Glycolysis. PLoS Pathog 12:e1005648
Nicol, Samantha M; Sabbah, Shereen; Brulois, Kevin F et al. (2016) Primary B Lymphocytes Infected with Kaposi's Sarcoma-Associated Herpesvirus Can Be Expanded In Vitro and Are Recognized by LANA-Specific CD4+ T Cells. J Virol 90:3849-3859
Lee, Hye-Ra; Choi, Un Yung; Hwang, Sung-Woo et al. (2016) Viral Inhibition of PRR-Mediated Innate Immune Response: Learning from KSHV Evasion Strategies. Mol Cells 39:777-782
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

Showing the most recent 10 out of 30 publications