Kaposi's sarcoma-associated herpes virus (KSHV), an important human pathogen accounting for a Large percentage of virally-caused cancers worldwide, has evolved a variety of stratagems for evading host immune responses to establish a life-long persistent infection and for deregulating cell growth control to achieve oncogenesis. The goal of Project 1 is to better understand how the KSHV evades host's innate and adaptive immune controls and subsequently deregulates host's growth controls, with a specific focus on the KSHV K3 and K5 genes. Our preliminary study has shown (1) that both the K3 and K5 membrane E3 ubiquitin ligase proteins downregulate MHC class I and CDId molecules, and the K5 downregulates numerous immune modulatory proteins (interferon gamma receptor 1, B7-2, ICAM-1, tetherin etc.). We have also discovered (2) that the K3 or K5 expression apparently increases cell proliferation and induced tumorigenicity in nude mice, and (3) that the K5 gene whose promoter carries an active epigenetic mark during latency is readily expressed in Kaposi's Sarcoma tumors, as well as in Primary Effusion Lymphomas and multicastleman's diseases. (4) Furthermore, we have developed an """"""""infectious"""""""" KSHV bacterial artificial chromosome (BAC16) to facilitate the efficient genetic manipulation ofthe viral genome. A main hypothesis of Project 1 is that the KSHV has evolved to carry the K3 and K5 genes with similar, yet distinct biochemical activities to ensure comprehensive protection from host immune effectors and to deregulate cell growth control. Despite previous extensive cell biology and biochemical studies, the detailed in vivo biological evidences of K3- and K5-mediated immune evasion in viral persistence and pathogenesis are still elusive. In this proposal, we will attempt to define in vivo roles ofthe K3 and K5 in vial persistence and oncogenesis. Specifically, we will test whether the loss of K3 and/or K5 genes from the KSHV genome affects the establishment of viral persistence in NOD/SCID IL2Ry-/- """"""""humanized"""""""" mice and the induction of viral oncogenic transformation of primary embryonic mesenchymal stem cells (MSC) in cultures and nude mice. This proposal is highly innovative and its successful outcome should significantly impact our understanding of KSHV biology.

Public Health Relevance

Host immune responses play essential roles in the suppression of viral infection/replication and the elimination of viruses from infected hosts. To avoid these host innate and adaptive immune responses, herpes viruses have evolved elaborate mechanisms to target and modulate differing aspects of the host's immune systems, which ultimately lead to persistent infection and pathogenesis. Thus, understanding KSHV-mediated immune evasion tricks and pathogenesis tactics is the primary goal of this application.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA180779-01
Application #
8740965
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Project Start
2013-08-13
Project End
2018-07-31
Budget Start
2013-08-13
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$362,536
Indirect Cost
$155,035
Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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 90:3849-59
Li, Wan; Jia, Xuemei; Shen, Chenyou et al. (2016) A KSHV microRNA enhances viral latency and induces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway. Oncotarget 7:32286-305
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
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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
Zhao, Jun; Li, Junhua; Xu, Simin et al. (2016) Emerging Roles of Protein Deamidation in Innate Immune Signaling. J Virol 90:4262-8
Li, Wan; Yan, Qin; Ding, Xiangya et al. (2016) The SH3BGR/STAT3 Pathway Regulates Cell Migration and Angiogenesis Induced by a Gammaherpesvirus MicroRNA. PLoS Pathog 12:e1005605
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
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

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