Abstract

Human herpesvirus-8 (HHV-8), a member of the gamma subfamily of herpesviruses, is associated with malignancies including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The mechanism(s) by which the virus causes cancers is not yet clear. Cellular IL-6 is up-regulated in all of these tumors and the tumor cells are responsive to cellular IL-6. IL-6 is a multifunctional cytokine, important for cell survival, proliferation, and differentiation. Strikingly, HHV-8 and several related herpesviruses encode a homologue of IL-6. Viral IL-6 was found expressed in KSHV-related tumor cells. Viral IL-6 was able to activate the Jak/STAT pathway and support the proliferation of both human and murine B cells in vitro. However, interleukins usually function in the context of a complicated network in the body. Such complicated in vivo interactions cannot be reproduced well in vitro. Furthermore, there is no effective in vitro lytic replication for KSHV. Therefore, this application proposes to use MHV-68 as a model system to define the role of viral and cellular IL-6 in viral replication and related pathogenesis. MHV-68 is closely related to HHV-8 but does not encode an IL-6 homologue. A viral IL-6 expression cassette will be inserted into MHV-68. The function of viral IL-6 during viral replication in vitro and in vivo will be assessed and the underlying mechanism will be explored. The available knock-out mice will allow us to study the contributions of cellular factors in viral replication in vivo. This proposal, on the basis of our preliminary data, is to test the hypothesis that acquiring interleukin-6 onto the viral genome offers an advantage for viral replication and will aid us in understanding the role of cellular IL-6 and viral IL-6 in related pathogenesis. MHV-68 can form plaques on fibroblast cells in culture and infect mice in a controllable manner, which offers a unique experimental advantage. Our continuous study will be critical to reveal the function of cellular and viral IL-6, a pair of intriguing and important molecules in the life cycle of KSHV.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015752-03
Application #
6891387
Study Section
Special Emphasis Panel (ZRG1-AARR-4 (02))
Program Officer
Mcinnes, Pamela M
Project Start
2003-07-21
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$325,994
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Pharmacology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Wong-Ho, Elaine; Wu, Ting-Ting; Davis, Zoe H et al. (2014) Unconventional sequence requirement for viral late gene core promoters of murine gammaherpesvirus 68. J Virol 88:3411-22
Gong, Danyang; Wu, Nicholas C; Xie, Yafang et al. (2014) Kaposi's sarcoma-associated herpesvirus ORF18 and ORF30 are essential for late gene expression during lytic replication. J Virol 88:11369-82
Wu, Ting-Ting; Qian, Jing; Ang, Jian et al. (2012) Vaccine prospect of Kaposi sarcoma-associated herpesvirus. Curr Opin Virol 2:482-8
Wu, Ting-Ting; Liao, Hsiang-I; Tong, Leming et al. (2011) Construction and characterization of an infectious murine gammaherpesivrus-68 bacterial artificial chromosome. J Biomed Biotechnol 2011:926258
Jia, Qingmei; Freeman, Michael L; Yager, Eric J et al. (2010) Induction of protective immunity against murine gammaherpesvirus 68 infection in the absence of viral latency. J Virol 84:2453-65
Freeman, Michael L; Lanzer, Kathleen G; Cookenham, Tres et al. (2010) Two kinetic patterns of epitope-specific CD8 T-cell responses following murine gammaherpesvirus 68 infection. J Virol 84:2881-92
Wu, Ting-Ting; Blackman, Marcia A; Sun, Ren (2010) Prospects of a novel vaccination strategy for human gamma-herpesviruses. Immunol Res 48:122-46
Peng, Li; Ryazantsev, Sergey; Sun, Ren et al. (2010) Three-dimensional visualization of gammaherpesvirus life cycle in host cells by electron tomography. Structure 18:47-58
Wu, Ting-Ting; Park, Tina; Kim, Hana et al. (2009) ORF30 and ORF34 are essential for expression of late genes in murine gammaherpesvirus 68. J Virol 83:2265-73
Hwang, Seungmin; Kim, Kyeong Seon; Flano, Emilio et al. (2009) Conserved herpesviral kinase promotes viral persistence by inhibiting the IRF-3-mediated type I interferon response. Cell Host Microbe 5:166-78

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