Kaposi's sarcoma-associated herpesvirus (KSHV) belongs to the lymphotropic gamma herpesviridae. In immunocompromised patients, such as organ transplant recipients and AIDS patients, KSHV infection is invariantly associated with Kaposi's sarcoma, a skin angiogenic neoplasm. Additionally, KSHV is the etiological agent for two rare lymphoproliferative diseases, primary effusion lymphoma and multicentric Castleman's disease. The oncogenic potential and relatively ubiquitous infection imposes an eminent health threat worldwide. Understanding fundamental virology and host immune response are two sides of the same coins of KSHV infection and will pave new avenues to treat KSHV-associated malignancies. Innate immunity is the first line of defense against invading pathogens. Recent advances have outlined the framework of signal transduction in mounting host innate immune response. However, the specific functions of key innate immune components, e.g., the IKK-related kinase IKKe, remain contentious. We have recently discovered that the IKKs kinase restricts gamma herpesvirus lytic replication and enables latent/persistent infection. This study proposes to investigate the molecular mechanisms by which the IKKE kinase negates KSHV lytic replication, thereby enabling persistent infection! We will characterize virus-host interactions involving the IKKe kinase (Aim 1), define the regulatory action of IKKs on KSHV lytic replication (Aim 2), and finally assess the roles of IKKe and viral interactions thereof in KSHV persistent infection using a "humanized" mouse model. This proposal entails a powerful reverse genetic system to perturb virus-host interactions and investigate the roles of these interactions in KSHV lytic replication and persistent infection. The application of lytic replicating system and an animal model will identify key interactions and define mutual regulations of in vivo KSHV infection, instructing us on new ways to contain KSHV infection.

Public Health Relevance

Viral infection accounts for approximately 15% of cancers worldwide. Human herpesviruses are ubiquitous pathogens and, particularly, gamma herpesviruses are capable of promoting tumor formation under immuno-suppressed conditions. Our studies strive to investigate ways how viruses interact with host immune system, with an emphasis in viral surviving, evading, and even exploiting innate immune responses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA180779-01
Application #
8740968
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
$362,535
Indirect Cost
$155,035
Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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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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