antagonism of host antiviral responses by kaposis sarcoma-associated herpesvirus tegument protein orf45拮抗宿主抗病毒反应由卡波济氏肉瘤相关疱疹病毒蛋白质orf45外皮.pdfVIP

Antagonism of Host Antiviral Responses by Kaposi’s Sarcoma-Associated Herpesvirus Tegument Protein ORF45 1 2 2 Fan Xiu Zhu , Narayanan Sathish , Yan Yuan * 1 Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America, 2 Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America Abstract Virus infection of a cell generally evokes an immune response by the host to defeat the intruder in its effort. Many viruses have developed an array of strategies to evade or antagonize host antiviral responses. Kaposi’s sarcoma-associated herpesvirus (KSHV) is demonstrated in this report to be able to prevent activation of host antiviral defense mechanisms upon infection. Cells infected with wild-type KSHV were permissive for superinfection with vesicular stomatitis virus (VSV), suggesting that KSHV virions fail to induce host antiviral responses. We previously showed that ORF45, a KSHV immediate- early protein as well as a tegument protein of virions, interacts with IRF-7 and inhibits virus-mediated type I interferon induction by blocking IRF-7 phosphorylation and nuclear translocation (Zhu et al., Proc. Natl. Acad. Sci. USA. 99:5573-5578, 2002). Here, using an ORF45-null recombinant virus, we demonstrate a profound role of ORF45 in inhibiting host antiviral responses. Infection of cells with an ORF45-null mutant recombinant KSHV (BAC-stop45) triggered an immune response that resisted VSV super-infection, concomitantly associated with appreciable increases in transcription of type I IFN and downstream anti-viral effector genes. Gain-of-function analysis showed that ectopic expression of ORF45 in human fibrob