In Vivo Analysis of Viral Cyclin: Infection by herpesviruses causes an acute lytic infection that is rapidly cleared, and subsequent establishment of a latent infection that exists in balance with the host immune system for the lifetime of a healthy host. The gammaherpesviruses include the human pathogens, Epstein Barr virus and Kaposi's sarcoma herpesvirus, and the murine gammaherpesvirus-68 (gHV68). These viruses are related by sequence conservation, genomic organization, tropism, and associated pathologies. Latently infected cells express a limited set of viral genes, yet remain capable of reactivating lytic infection upon stimulation. Latency and reactivation from latency are associated with chronic disease and malignancies, particularly in immunocompromised hosts. Regulation of viral infection is a complex relationship between host and viral factors. These processes, from initial infection to latency and reactivation, are not well understood and have been constrained by the difficulties of studying higher mammalian host systems. The murine gHV68 model system provides a tractable small animal model in which both pathogen and host are genetically manipulable, and enables study of virus and host interactions through the entire course of viral infection. Previous utilization of gHV68 as a model system to study cell cycle regulation in viral infection demonstrated that the gHV68 viral cyclin promotes cell cycle progression and acts as an oncogene when expressed as a transgene in primary lymphocytes. The gHV68 viral cyclin is not required for any aspect of lytic infection, but is essential for efficient reactivation from latency. This proposal will address the mechanism of action of the gHV68 viral cyclin in infection. First, what is the expression pattern of the viral cyclin in infection? Second, what are the catalytic partners and the substrates of the viral cyclins in vivo? Third, are the unique features of the viral cyclins essential to their role in viral infection?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA103632-05S1
Application #
7576539
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Ogunbiyi, Peter
Project Start
2004-04-15
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2010-02-28
Support Year
5
Fiscal Year
2008
Total Cost
$49,804
Indirect Cost
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Kimball, Abigail K; Oko, Lauren M; Bullock, Bonnie L et al. (2018) A Beginner's Guide to Analyzing and Visualizing Mass Cytometry Data. J Immunol 200:3-22
Williams, Lisa M; Niemeyer, Brian F; Franklin, David S et al. (2015) A Conserved Gammaherpesvirus Cyclin Specifically Bypasses Host p18(INK4c) To Promote Reactivation from Latency. J Virol 89:10821-31
Diebel, Kevin W; Claypool, David J; van Dyk, Linda F (2014) A conserved RNA polymerase III promoter required for gammaherpesvirus TMER transcription and microRNA processing. Gene 544:8-18
Wu, Qun; van Dyk, Linda F; Jiang, Di et al. (2013) Interleukin-1 receptor-associated kinase M (IRAK-M) promotes human rhinovirus infection in lung epithelial cells via the autophagic pathway. Virology 446:199-206
Rubtsova, Kira; Rubtsov, Anatoly V; van Dyk, Linda F et al. (2013) T-box transcription factor T-bet, a key player in a unique type of B-cell activation essential for effective viral clearance. Proc Natl Acad Sci U S A 110:E3216-24
Getahun, Andrew; Smith, Mia J; Kogut, Igor et al. (2012) Retention of anergy and inhibition of antibody responses during acute ? herpesvirus 68 infection. J Immunol 189:2965-74
Klionsky, Daniel J (see original citation for additional authors) (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8:445-544
Lee, Katherine S; Suarez, Andrea L; Claypool, David J et al. (2012) Viral cyclins mediate separate phases of infection by integrating functions of distinct mammalian cyclins. PLoS Pathog 8:e1002496
Larson, Jennifer D; Thurman, Joshua M; Rubtsov, Anatoly V et al. (2012) Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity. Proc Natl Acad Sci U S A 109:E1092-100
Orioli, Andrea; Pascali, Chiara; Quartararo, Jade et al. (2011) Widespread occurrence of non-canonical transcription termination by human RNA polymerase III. Nucleic Acids Res 39:5499-512

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