The gammaherpesviruses establish lifelong latency in the human host. Kaposi's sarcoma-associated herpesviruses (KSHV) and Epstein-Barr Virus (EBV) are members of this family. These viruses are associated with several different cancers in the human population, are present in the oral cavity, and can be transmitted orally. The gammaherpesviruses establish life-long latency in the host. During latency the viral genome is chromatinized by host factors, and viral gene expression is extremely limited during latency. However during viral reactivation, many of the chromatin modifications are changed resulting in the transcription and expression of many more viral genes. We have recently performed a siRNA screen and identified a novel cellular kinase, tousled like kinase (TLK) that is involved in regulating the gammaherpesviral latent-lytic switch and modulating the host genome. In response to RFA-DE-13-002, we propose to understand how TLK regulates the viral epigenome to augment latency and suppress reactivation. Understanding of the mechanism involved in governing gammaherpesviral latency and reactivation is relevant to oral cancer and oral disease associated with replication of these viruses. Our investigation may help guide novel therapies for treatment of oral disease.

Public Health Relevance

The gammaherpesviruses establish lifelong latency in the human host. Kaposi's sarcoma-associated herpesviruses (KSHV) and Epstein-Barr Virus (EBV) are members of this family. These viruses are associated with several different cancers in the human population, are present in the oral cavity, and can be transmitted orally. The gammaherpesviruses establish life-long latency in the host. During latency the viral genome is chromatinized by host factors, and viral gene expression is extremely limited during latency. However during viral reactivation, many of the chromatin modifications are changed resulting in the transcription and expression of many more viral genes. We have recently performed a siRNA screen and identified a novel cellular kinase, tousled like kinase (TLK) that is involved in regulating the gammaherpesviral latent-lytic switch and modulating the host genome. In response to RFA-DE-13-002, we propose to understand how TLK regulates the viral epigenome to augment latency and suppress reactivation. Understanding of the mechanism involved in governing gammaherpesviral latency and reactivation is relevant to oral cancer and oral disease associated with replication of these viruses. Our investigation may help guide novel therapies for treatment of oral disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
4R01DE023946-04
Application #
9113540
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Lunsford, Dwayne
Project Start
2013-09-17
Project End
2018-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Dittmer, Dirk P; Tamburro, Kristen; Chen, Huichao et al. (2017) Oral shedding of herpesviruses in HIV-infected patients with varying degrees of immune status. AIDS 31:2077-2084
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Speicher, D J; Ramirez-Amador, V; Dittmer, D P et al. (2016) Viral infections associated with oral cancers and diseases in the context of HIV: a workshop report. Oral Dis 22 Suppl 1:181-92
Dittmer, Dirk P; Damania, Blossom (2016) Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest 126:3165-75
Dittmer, Dirk P; Damania, Blossom; Sin, Sang-Hoon (2015) Animal models of tumorigenic herpesviruses--an update. Curr Opin Virol 14:145-50
Ma, Zhe; Jacobs, Sarah R; West, John A et al. (2015) Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses. Proc Natl Acad Sci U S A 112:E4306-15

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