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.
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