The proposed research is directed toward investigating KSHV immune evasion strategies, specifically focused with the roles of viral interferon regulatory factor (vIRF)-mediated deregulation of IFN response and growth control for KSHV persistence and pathogenesis. Our previous studies have demonstrated how KSHV comprehensively inhibits host IFN-mediated signal transduction and deregulates growth control: (1) vIRF1 downregulates cellular IRF3 and p53 transcriptional activity by interacting with p300 transcriptional coactivator and ATM kinase, respectively;(2) vIRF3 inhibits IRF7 by suppressing its DNA binding activity and induces angiogenesis by enhancing HIF11 stability;(3) vIRF4 downregulates IFN1 gene expression and upregulates translational control. Furthermore, we have shown how host elicits IFN signal transduction upon viral infection. Finally, we have successfully developed the non-human primate for KSHV persistent infection. We would stress that this is the first animal model that significantly recapitulates important aspects of KSHV infection in human and thus provides a unique opportunity to dissect the molecular mechanisms of KSHV infection and persistence directly in primate. To further unravel how KSHV establishes a life-long infection, we continuously investigate a novel viral strategy that KSHV vIRFs deregulate host innate immunity and cell growth control to establish persistent infection. Our biochemical and cell biology studies will define in greater detail the molecular mechanisms used by vIRFs to inhibit IFN-mediated innate immunity and host p53 tumor suppressor-mediated cell growth control. To correlate the effects of vIRFs on IFN response and cell growth regulation with viral life cycle in vivo, we will then test how the loss of vIRF gene(s) affects the KSHV persistent infection in primates. With well-established in vitro and in vivo experimental conditions, the proposed study will detail the roles of vIRFs, IFN antagonist and cell growth deregulator, in viral persistence. This proposal is highly innovative and the successful outcome should be a major discovery that significantly impacts the understanding of KSHV biology and may reveal targets for novel therapeutic strategies.

Public Health Relevance

Most viruses have evolved immune evasion strategies to protect themselves against host interferon (IFN) responses, elaborating viral proteins as a counter-defense against the host IFN defenses. During the last granting period, we have demonstrated a novel mechanism of KSHV to antagonize cellular IFN-mediated anti-viral activity by incorporating viral homologs to the cellular interferon regulatory factors (IRFs), and have also developed a primate model for KSHV persistent infection that significantly recapitulates important aspects of KSHV infection in human. To further unravel how KSHV establishes a life-long infection, we will continuously investigate a novel viral immune evasion strategy that KSHV vIRFs deregulate host IFN-mediated innate immunity and tumor suppressor-mediated cell growth control to establish persistent infection.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082057-14
Application #
8256542
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1999-06-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
14
Fiscal Year
2012
Total Cost
$324,583
Indirect Cost
$124,223
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
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
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
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
Cheng, Fan; Sawant, Tanvee Vinod; Lan, Ke et al. (2015) Screening of the Human Kinome Identifies MSK1/2-CREB1 as an Essential Pathway Mediating Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication during Primary Infection. J Virol 89:9262-80
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
Jung, Jae; Münz, Christian (2015) Immune control of oncogenic γ-herpesviruses. Curr Opin Virol 14:79-86

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