Despite being a significant human health problem, a majority of KSHV studies have been restricted to the overexpression system of the selected viral genes in the absence of viral complete genome and Infection, leading to limited understanding to in vivo KSHV persistence and pathogenesis that are essential in developing safe and effective anti-viral agents and vaccines against this oncogenic pathogen. Specifically, understanding how KSHV gene products contribute to the establishment of persistent infection and pathogenesis requires a reverse genetics approach for the viral genetic deficiencies, an in vitro and in vivo assay system for the viral oncogenesis, and an animal model for the in vivo viral persistence under active host immune conditions. Fortunately, our Program Project Grant (PPG) leaders have recently established a new """"""""infectious"""""""" bacterial artificial clone (BACI6) of KSHV genome that significantly improves the efficiency of the genetic manipulation and virus production (Project 1), a novel system to investigate host's control of the KSHV nucleotide metabolism (Project 2), an efficient KSHV infection and transformation system using primary embryonic metanephric mesenchymal stem cells (MSC cells) (Project 3), and a well-controlled in vivo infection system using a humanized mouse model where KSHV establishes persistent infection and is disseminated into the B and monocyte lineages (Core). Thusly, this multi-disciplinary PPG application is directed toward investigating the host's tricks of Immune recognition and attack as well as the KSHV's tactics of immune evasion and pathogenesis by utilizing recently developed """"""""infectious"""""""" KSHV genetic system, in vitro and in vivo transformation assays, and in vivo humanized mouse models. The major goal of this multi-project grant application is to address (1) how hosts have developed effective mechanisms necessary to control KSHV infection and replication, (2) how KSHV has evolved the various mechanisms necessary to thwart and exploit the host defenses, and (3) how KSHV has conferred the infected cells with oncogenic signatures. This application consists of three Projects with multidisciplinary focused schemes. In addition, the Cores provide an efficient genetic manipulation system for KSHV mutagenesis, a state-of-art humanized mouse model for KSHV persistence and a MSC cell/nude mouse system for KSHV oncogenesis and the Administrative Core provides the overall program milestone and data dissemination.

Public Health Relevance

In order to improve our capability of responding to this emerging cancer in immunosuppressed patients more quickly and effectively, we will improve our understanding of how hosts and KSHV combat each other and how KSHV persists in the immune compromised hosts.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA180779-01
Application #
8603056
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Program Officer
Read-Connole, Elizabeth Lee
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
$1,463,663
Indirect Cost
$571,412
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
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
Zhang, Junjie; Feng, Hao; Xu, Simin et al. (2016) Hijacking GPCRs by viral pathogens and tumor. Biochem Pharmacol 114:69-81
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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