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.
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.
|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 90:6515-25|
|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|
|Liang, Qiming; Luo, Zhifei; Zeng, Jianxiong et al. (2016) Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy. Cell Stem Cell 19:663-671|
|Zhang, Junjie; He, Shanping; Wang, Yi et al. (2015) Herpesviral G protein-coupled receptors activate NFAT to induce tumor formation via inhibiting the SERCA calcium ATPase. PLoS Pathog 11:e1004768|
|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|
|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|
Showing the most recent 10 out of 21 publications