Many, if not all members of the Herpes and Polyoma virus families encode microRNAs (miRNAs). miRNAs function by binding to specific viral or cellular target mRNAs and inhibiting their expression. miRNA- mediated gene regulation has been implicated in important cellular processes such as tumorigenesis. Recent work from our laboratory has demonstrated that the miRNAs encoded by Simian Virus 40 (SVmiRNA) function to provide a growth advantage to infected cells undergoing an interferon response. Furthermore, expression of the gene encoding the SVmiRNAs prevents interferon-mediated apoptosis, implying an important role in evading a host antiviral defense. We have also uncovered several oncogenic cellular miRNAs that are induced upon infection with SV40. Although this work points to an important role for miRNAs in DNA tumor viral lifecycles, the mechanism of how SV40 induces expression of viral and cellular miRNAs and how this prevents apoptosis and contributes to transformation is not understood. The goal of this proposal is to determine the contribution of miRNAs to Polyomaviral infectivity and viral-induced transformation. To this end, three specific aims are proposed.
These specific aims propose genetic and biochemical techniques to: (1) Identify the components of the interferon pathway that are responsible for Polyomaviral-induced apoptosis. (2) Determine the mechanism by which the Polyomaviral miRNA gene products prevent interferon-induced apoptosis. (3) Determine the role of virally-induced oncogenic cellular miRNAs in Polyomavirus replication and transformation.

Public Health Relevance

Viral-mediated gene regulation is critical for pathogenicity. The goal of this project is to understand the role of microRNA-mediated gene regulation in the Simian Virus 40-induced transformation and the infectious cycle. Knowledge generated from this research may be applicable to other DNA tumor viruses and their associated human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077746-04
Application #
8317622
Study Section
Virology - B Study Section (VIRB)
Program Officer
Park, Eun-Chung
Project Start
2009-09-07
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$266,341
Indirect Cost
$82,828
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Burke, James M; Kincaid, Rodney P; Nottingham, Ryan M et al. (2016) DUSP11 activity on triphosphorylated transcripts promotes Argonaute association with noncanonical viral microRNAs and regulates steady-state levels of cellular noncoding RNAs. Genes Dev 30:2076-2092
Cox, Jennifer E; McClure, Lydia V; Goga, Andrei et al. (2015) Pan-viral-microRNA screening identifies interferon inhibition as a common function of diverse viruses. Proc Natl Acad Sci U S A 112:1856-61
Chen, Chun Jung; Cox, Jennifer E; Azarm, Kristopher D et al. (2015) Identification of a polyomavirus microRNA highly expressed in tumors. Virology 476:43-53
Burke, James M; Bass, Clovis R; Kincaid, Rodney P et al. (2014) Identification of tri-phosphatase activity in the biogenesis of retroviral microRNAs and RNAP III-generated shRNAs. Nucleic Acids Res 42:13949-62
Pare, Justin M; Sullivan, Christopher S (2014) A host MicroRNA brokers truce with HSV-1. Cell Host Microbe 15:395-7
Zhang, Shaojie; Sroller, Vojtech; Zanwar, Preeti et al. (2014) Viral microRNA effects on pathogenesis of polyomavirus SV40 infections in syrian golden hamsters. PLoS Pathog 10:e1003912
Kincaid, Rodney P; Chen, Yating; Cox, Jennifer E et al. (2014) Noncanonical microRNA (miRNA) biogenesis gives rise to retroviral mimics of lymphoproliferative and immunosuppressive host miRNAs. MBio 5:e00074
Burke, James M; Kelenis, Demetra P; Kincaid, Rodney P et al. (2014) A central role for the primary microRNA stem in guiding the position and efficiency of Drosha processing of a viral pri-miRNA. RNA 20:1068-77
Pare, Justin M; Sullivan, Christopher S (2014) Distinct antiviral responses in pluripotent versus differentiated cells. PLoS Pathog 10:e1003865
Chen, Chun Jung; Burke, James M; Kincaid, Rodney P et al. (2014) Naturally arising strains of polyomaviruses with severely attenuated microRNA expression. J Virol 88:12683-93

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