This R01 application is in response to RFA-DE-07-002 to study the long-term use of antiretroviral therapy (ART) on the oral mucosa. Specifically, we will investigate how changes in the oropharyngeal tissues contribute to the pathogenesis of the human herpes viruses HSV-1, EBV and KSHV. These human pathogens cause different disease phenotype ranging from tissue destructive viremia (HSV-1) to oral cancer (KSHV, EBV). Regardless though of the final pathology, reactivation from a viral latent state seems to precede disease, and in case of EBV and KSHV many of the disease phenotypes are caused by gene products that are only expressed during viral reactivation. We hypothesize that (a) changes in the oral mucosal epithelial surfaces cause virus reactivation and (b) that ART modulates both the physiological trigger and the viral gene profile leading to ART-associated viral diseases such as oral KS, which is hardly seen in HIV-negative, ART-negative so called classic KS patients or EBV-positive plasmablastic lymphomas of the lower jaw. Furthermore, we will explore the effect of ART drugs on the innate immune response, i.e. TLR signaling by using our recently developed NF-kappaB real-time QPCR array to compare both clinical samples and experimental models of buccal and gingival epithelium.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE018304-04
Application #
7835669
Study Section
Special Emphasis Panel (ZDE1-PZ (19))
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2007-05-15
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$314,490
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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Ma, Zhe; Hopcraft, Sharon E; Yang, Fan et al. (2017) NLRX1 negatively modulates type I IFN to facilitate KSHV reactivation from latency. PLoS Pathog 13:e1006350
Dittmer, Dirk P; Krown, Susan E; Mitsuyasu, Ronald (2017) Exclusion of Kaposi Sarcoma From Analysis of Cancer Burden. JAMA Oncol 3:1429
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McVoy, Michael A; Wang, Jian Ben; Dittmer, Dirk P et al. (2016) Repair of a Mutation Disrupting the Guinea Pig Cytomegalovirus Pentameric Complex Acquired during Fibroblast Passage Restores Pathogenesis in Immune-Suppressed Guinea Pigs and in the Context of Congenital Infection. J Virol 90:7715-27

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