Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically linked to Kaposi's sarcoma (KS), the most common malignancy and oral cancer in HIV/AIDS patients. In Africa, because of the severe AIDS epidemic and high prevalence (nearly 50%) of KSHV infection in some regions, KS accounts for nearly half of the reported cancers and is the leading cause of cancer death in those areas. KSHV establishes latent infection in the majority of infected cells in the KS lesion, but spontaneous lytic replications occur in a small fraction. Both clinical and experimental observations suggest that the ongoing lytic replication cycle of KSHV is continuously required for KS development. Recurring reactivation and infection episodes in KS lesion could trigger host antiviral responses, including interferon signaling, that would inevitably lead to repression of viral replication and elimination of virus-infected cells by apoptosis or subsequently activated adaptive immune responses. As obligate intracellular parasites, viruses rely on cellular signaling pathways for completion of their life cycles, but they often alter the signaling strength, duration, and target specificity to their own advantage. Therefore, evasion of host antiviral responses and modulation of the host cellular environment are two extremely important tasks for the virus. KSHV immediate-early and tegument protein ORF45 is in the forefront of coping with the host cellular environment because of its unique temporal and spatial expression. We have shown that ORF45 is involved in evasion of host interferon antiviral responses through inactivation of interferon regulatory factor 7 (IRF7) and modulation of the ERK MAPK signaling pathway through formation of complexes with p90 ribosomal S6 kinases (RSKs). With BAC-based mutagenesis, we have demonstrated that ORF45 has important functions at both early and late stages of viral infection. In the next budget period, (1) we will continue to investigate the mechanisms by which ORF45 evades host antiviral responses. We found that ORF45 makes full use of cellular negative regulation mechanisms particularly sumoylation to limit IRF7 activation. We will investigate how ORF45 exploits sumoylation as a strategy to suppress IRF7 activation and to antagonize host antiviral responses. (2) We will define the functional roles of sustained activation of ERK/RSK signaling by ORF45 in the KSHV lytic cycle. We have shown that the ORF45/RSK axis is required for KSHV lytic replication, but its exact roles are unclear. We will characterize a mutant virus carrying a RSK activation-deficient point mutation in ORF45. We will also identify the functional substrates of activated RSK and ERK and the additional components in the ORF45-induced cellular complexes. Our research will provide significant insights into viral reactivation, immune evasion, and modulation of host cellular-signaling pathways and will reveal novel mechanisms that KSHV uses to defeat host immune defenses and to modulate host cellular-signaling pathways. Understanding the interplay between the virus and host will facilitate development of novel therapeutic strategies for treatment of KSHV-associated diseases.

Public Health Relevance

KSHV has been linked to several human cancers. The goal of the studies proposed here is to investigate the mechanisms that KSHV uses to defeat the host antiviral defenses and to modulate cellular signaling pathways during its life cycle. Better understanding of the interplay between the virus and the host will facilitate identification of intervention targets and development of novel therapeutic strategies for KSHV-associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE016680-07
Application #
8249377
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2005-01-15
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
7
Fiscal Year
2012
Total Cost
$285,852
Indirect Cost
$85,852
Name
Florida State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
790877419
City
Tallahassee
State
FL
Country
United States
Zip Code
32306
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 90:5329-42
Sexton, Brittany S; Druliner, Brooke R; Vera, Daniel L et al. (2016) Hierarchical regulation of the genome: global changes in nucleosome organization potentiate genome response. Oncotarget 7:6460-75
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 90:5953-64
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
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
Avey, Denis; Brewers, Brittany; Zhu, Fanxiu (2015) Recent advances in the study of Kaposi's sarcoma-associated herpesvirus replication and pathogenesis. Virol Sin 30:130-45
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
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
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
Wu, Jian-Jun; Avey, Denis; Li, Wenwei et al. (2015) 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

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