Recent studies have revealed the importance of the oral environment in the dissemination of Kaposi's sarcoma-associated herpesvirus (KSHV) and the progression to KSHV-associated disease such as oral Kaposi's sarcoma. Oral epithelial cells have been shown to support lytic replication following primary infection and significant amount of transmissible infectious virions have been detected in saliva of KSHV-positive individuals. These studies also suggest that following replication in oral epithelial cells, KSHV may be transmitted into endothelial and B cells where it establishes latency. While latency and lytic reactivation of KSHV in endothelial and B cells have been extensively studied, little is known about the biology of KSHV replication in oral epithelial cells during de novo infection. Thus, the goal of this application is to identify characteristics of oral epithelial cells that predispose them to KSHV replication, which knowledge may help to develop novel strategies for prevention and treatment of oral complication by KSHV infection. We have previously shown that following de novo infection of gingival epithelial cells KSHV adopts a transcriptionally activ chromatin resulting in lytic gene expression and virus replication. Based on our findings we hypothesize that specific host epigenetic factors are recruited to the KSHV genome in oral epithelial cells, which make the viral chromatin permissive for viral transcription resulting in vial replication. In addition, KSHV infection can alter the expression of many cellular genes in oral epithelial cells, which can be critical for the sustained lytic viral replication following de novo infection. Thus, the aim of this pilot study is twofold: (i) to identify critical host epigenetic fctors that control the lytic replication of KSHV in oral epithelial cells, and (ii) to characterize the hst genes specifically altered in oral epithelial cells upon KSHV infection, which can shed light on what makes the oral epithelial cells susceptible for KSHV lytic replication. This NIDCR R03 grant for New Investigators is aimed to establish the preliminary data that is necessary to apply for a larger R01 grant. My future studies will determine the molecular mechanisms of how the identified host epigenetic factors regulate KSHV lytic replication in oral epithelial cells and whether they also play a role in the regulation of lytic reactivation in B cells in which KSHV exists predominantly in latency. Besides KSHV, other human pathogenic herpesviruses (e.g. HSV-1, HCMV, EBV) can also replicate in the oral cavity. Because their lytic replication mechanisms share many similarities with that of KSHV, we will also test whether other oral herpesviruses use the same host epigenetic factors for their replication.

Public Health Relevance

Kaposi's sarcoma-associated herpesvirus (KSHV) is a true oral herpesvirus, which is shed in the oral cavity and can lead to the development of oral Kaposi's sarcoma, the most common oral malignancy in AIDS patients and immunocompromised individuals. Despite the important health problem associated with KSHV infection, the dissemination of the virus in the oral cavity is still poorly understood. The goal o this application is to identify and characterize host epigenetic factors and KSHV-regulated host genes that are critical for the regulation of KSHV lytic replication in oral epithelial cells, and an be primarily responsible for the spreading of the virus in the mouth.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Small Research Grants (R03)
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NIDR Special Grants Review Committee (DSR)
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Rodriguez-Chavez, Isaac R
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University of Southern California
Schools of Medicine
Los Angeles
United States
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Brice, David C; Toth, Zsolt; Diamond, Gill (2018) LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells. Antiviral Res 158:25-33
Toth, Zsolt; Smindak, Richard J; Papp, Bernadett (2017) Inhibition of the lytic cycle of Kaposi's sarcoma-associated herpesvirus by cohesin factors following de novo infection. Virology 512:25-33
Toth, Zsolt; Papp, Bernadett; Brulois, Kevin et al. (2016) LANA-Mediated Recruitment of Host Polycomb Repressive Complexes onto the KSHV Genome during De Novo Infection. PLoS Pathog 12:e1005878