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 #
5P01CA180779-02
Application #
8755899
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Liang, Qiming; Wei, Dahai; Chung, Brian et al. (2018) Novel Role of vBcl2 in the Virion Assembly of Kaposi's Sarcoma-Associated Herpesvirus. J Virol 92:
Foo, Suan-Sin; Chen, Weiqiang; Chan, Yen et al. (2018) Biomarkers and immunoprofiles associated with fetal abnormalities of ZIKV-positive pregnancies. JCI Insight 3:
Zhang, Junjie; Zhao, Jun; Xu, Simin et al. (2018) Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication. Cell Host Microbe 24:234-248.e5
Foo, Suan-Sin; Chen, Weiqiang; Chan, Yen et al. (2017) Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy. Nat Microbiol 2:1558-1570
Yuan, Hongfeng; Tan, Brandon; Gao, Shou-Jiang (2017) Tenovin-6 impairs autophagy by inhibiting autophagic flux. Cell Death Dis 8:e2608
Hwang, Sung-Woo; Kim, DongIk; Jung, Jae U et al. (2017) KSHV-encoded viral interferon regulatory factor 4 (vIRF4) interacts with IRF7 and inhibits interferon alpha production. Biochem Biophys Res Commun 486:700-705
Yuan, Hongfeng; He, Meilan; Cheng, Fan et al. (2017) Tenovin-6 inhibits proliferation and survival of diffuse large B-cell lymphoma cells by blocking autophagy. Oncotarget 8:14912-14924
Zhu, Ying; Li, Tingting; Ramos da Silva, Suzane et al. (2017) A Critical Role of Glutamine and Asparagine ?-Nitrogen in Nucleotide Biosynthesis in Cancer Cells Hijacked by an Oncogenic Virus. MBio 8:
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 90:3849-3859
He, Meilan; Yuan, Hongfeng; Tan, Brandon et al. (2016) SIRT1-mediated downregulation of p27Kip1 is essential for overcoming contact inhibition of Kaposi's sarcoma-associated herpesvirus transformed cells. Oncotarget 7:75698-75711

Showing the most recent 10 out of 67 publications