Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8), is a member of gamma-herpesvirus family, which characteristically establishes latent infection in lymphoid cells. Reactivation of lytic infection of KSHV from latently infected lymphoid reservoir seems a necessary antecedent step in the development of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). Therefore, the switch of the virus from latent to lytic cycle infection may be not only important for viral propagation, but also crucial for viral pathogenicity. The investigators' laboratory has been interested in the switch of KSHV from latency to lytic life cycle, and several KSHV immediate early (IE) genes have been recently identified in their lab (Zhu et al, 1999, Appendix A). Viral IE genes usually encode regulatory proteins that initiate and control the productive lytic cycle infection process. The long-term objective of this project is to understand the mechanism of the reactivation of KSHV and its roles in viral pathogenicity. This proposal will focus on two major immediate-early proteins of KSHV, namely ORF50 and ORF45. Emphasis will be placed on the modulation of host-virus interaction by these two IE proteins during the viral reactivation. (1) The ORF50 is a transcriptional activator known to be able to activate viral lytic genes. In the proposed studies, the researchers will investigate the role of ORF50 in altering host cellular gene expression and cell physiology. (2) The ORF45 was found to interact with cellular interferon regulatory factor-7 (IRF-7). IRF-7 is a transcription regulator, which is responsible for activation of interferon genes in response to viral infection. They will investigate whether ORF45 is a strategy that KSHV uses to target components of the host anti-viral defenses. (3) Finally, the expression of ORF50 and ORF45 will be specifically blocked by using a novel gene-inactivation technique, namely the external guide sequence (EGS), and the investigators will examine roles of ORF50 and ORF45 in KSHV lytic replication and pathogenicity. In addition, the results from the proposed studies will provide assessment of whether targeting KSHV IE proteins (especially ORF50) could be new strategies for therapeutic intervention of KSHV-associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA086839-04
Application #
6633755
Study Section
Special Emphasis Panel (ZRG1-AARR-4 (01))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2000-06-01
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
4
Fiscal Year
2003
Total Cost
$285,300
Indirect Cost
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Cramer, Elizabeth M; Shao, Ying; Wang, Yan et al. (2014) miR-190 is upregulated in Epstein-Barr Virus type I latency and modulates cellular mRNAs involved in cell survival and viral reactivation. Virology 464-465:184-195
Liang, Qiming; Fu, Bishi; Wu, Fayi et al. (2012) ORF45 of Kaposi's sarcoma-associated herpesvirus inhibits phosphorylation of interferon regulatory factor 7 by IKK? and TBK1 as an alternative substrate. J Virol 86:10162-72
González-Molleda, Lorenzo; Wang, Yan; Yuan, Yan (2012) Potent antiviral activity of topoisomerase I and II inhibitors against Kaposi's sarcoma-associated herpesvirus. Antimicrob Agents Chemother 56:893-902
Wang, Yan; Sathish, Narayanan; Hollow, Charles et al. (2011) Functional characterization of Kaposi's sarcoma-associated herpesvirus open reading frame K8 by bacterial artificial chromosome-based mutagenesis. J Virol 85:1943-57
Sathish, Narayanan; Zhu, Fan Xiu; Golub, Ellis E et al. (2011) Mechanisms of autoinhibition of IRF-7 and a probable model for inactivation of IRF-7 by Kaposi's sarcoma-associated herpesvirus protein ORF45. J Biol Chem 286:746-56
Sathish, Narayanan; Yuan, Yan (2011) Evasion and subversion of interferon-mediated antiviral immunity by Kaposi's sarcoma-associated herpesvirus: an overview. J Virol 85:10934-44
Zhu, Fan Xiu; Sathish, Narayanan; Yuan, Yan (2010) Antagonism of host antiviral responses by Kaposi's sarcoma-associated herpesvirus tegument protein ORF45. PLoS One 5:e10573
Sathish, Narayanan; Zhu, Fan Xiu; Yuan, Yan (2009) Kaposi's sarcoma-associated herpesvirus ORF45 interacts with kinesin-2 transporting viral capsid-tegument complexes along microtubules. PLoS Pathog 5:e1000332
Wang, Yan; Li, Hong; Tang, Qiyi et al. (2008) Kaposi's sarcoma-associated herpesvirus ori-Lyt-dependent DNA replication: involvement of host cellular factors. J Virol 82:2867-82
Rozen, Ramona; Sathish, Narayanan; Li, Yong et al. (2008) Virion-wide protein interactions of Kaposi's sarcoma-associated herpesvirus. J Virol 82:4742-50

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