This proposal is response to RFA-DE-05-001. Kaposi's sarcoma associated herpesvirus (KSHV) is etiologically linked to Kaposi's sarcoma (KS), the most common malignancy and oral cancer in AIDS patients. Unlike other DNA tumor viruses, KSHV lytic life cycle contributes significantly to the formation of KS lesions by facilitating viral spread to the target sites and releasing paracrine factors to support the growth of KS tumor cells. Recent study found that KSHV episomes in latently infected cells were rapidly lost due to cell proliferation, reactivation and infection processes constantly happen in KS lesion in order to maintain viral infected cell population. Reactivation and infection normally inevitably triggers host innate antiviral response including interferon (IFN) signaling pathway. However, KSHV evolved elaborate mechanism to evade IFN signaling which enable its recurring reactivation and infection process undetected by host immune surveillance system. We have found KSHV immediate early protein ORF45 interacts with cellular interferon regulatory factor-7 (IRF-7) and prohibits IRF-7 from being transported to the nucleus. As a result, ORF45 efficiently inhibits the induction of type I interferon during viral infection. In addition, ORF45 protein is also found in KSHV virion as tegument protein. The immediate-early expression kinetics as well as the presence of ORF45 in virion suggests critical roles of ORF45 in antagonizing host antiviral defenses and viral propagation. We hypothesize that KSHV uses ORF45 protein to ensure a protection from host immune responses and a successful viral infection and reactivation. In this proposal, first, we will investigate the mechanism that ORF45 use to block the IRF-7 activation and interferon induction. Second, we will examine the role of ORF45 in antagonizing host antiviral response with both gain-of-function and loss-of-function approach. Third, we will assess the impact of ORF45 on KSHV reactivation and pathogenicity by disrupting ORF45 gene function With SiRNA or recombinant ORF45 deficient KSHV. The proposed study will reveal the mechanism that viruses use to defeat host immune defenses and role of ORF45 in viral infection and pathogenesis. In addition, our research may also suggest novel therapeutic target and strategies in treatment of KSHV-associated malignancies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE016680-01
Application #
6912934
Study Section
Special Emphasis Panel (ZDE1-PZ (08))
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2005-01-15
Project End
2008-12-31
Budget Start
2005-01-15
Budget End
2005-12-31
Support Year
1
Fiscal Year
2005
Total Cost
$277,375
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
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Li, Wenwei; Avey, Denis; Fu, Bishi et al. (2016) Kaposi's Sarcoma-Associated Herpesvirus Inhibitor of cGAS (KicGAS), Encoded by ORF52, Is an Abundant Tegument Protein and Is Required for Production of Infectious Progeny Viruses. J Virol 90:5329-5342
Avey, Denis; Tepper, Sarah; Pifer, Benjamin et al. (2016) Discovery of a Coregulatory Interaction between Kaposi's Sarcoma-Associated Herpesvirus ORF45 and the Viral Protein Kinase ORF36. J Virol 90:5953-5964
Wu, Jian-Jun; Avey, Denis; Li, Wenwei et al. (2016) ORF33 and ORF38 of Kaposi's Sarcoma-Associated Herpesvirus Interact and Are Required for Optimal Production of Infectious Progeny Viruses. J Virol 90:1741-56
Wang, Xin; Zhu, Nannan; Li, Wenwei et al. (2015) Mono-ubiquitylated ORF45 Mediates Association of KSHV Particles with Internal Lipid Rafts for Viral Assembly and Egress. PLoS Pathog 11:e1005332
Wu, Jian-jun; Li, Wenwei; Shao, Yaming et al. (2015) Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein. Cell Host Microbe 18:333-44
Avey, Denis; Tepper, Sarah; Li, Wenwei et al. (2015) Phosphoproteomic Analysis of KSHV-Infected Cells Reveals Roles of ORF45-Activated RSK during Lytic Replication. PLoS Pathog 11:e1004993
Li, Xiaojuan; Du, Shumin; Avey, Denis et al. (2015) ORF45-Mediated Prolonged c-Fos Accumulation Accelerates Viral Transcription during the Late Stage of Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus. J Virol 89:6895-906
Fu, Bishi; Kuang, Ersheng; Li, Wenwei et al. (2015) Activation of p90 ribosomal S6 kinases by ORF45 of Kaposi's sarcoma-associated herpesvirus is critical for optimal production of infectious viruses. J Virol 89:195-207
Gillen, Joseph; Li, Wenwei; Liang, Qiming et al. (2015) A survey of the interactome of Kaposi's sarcoma-associated herpesvirus ORF45 revealed its binding to viral ORF33 and cellular USP7, resulting in stabilization of ORF33 that is required for production of progeny viruses. J Virol 89:4918-31

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