Clinical Manifestations and Epigenetic Regulation of Oral Herpesvirus Infections

Abstract

The oral cavity is often the first site where viruses interact with the human body. The oral epithelium is a major site of viral entry, replication and spread to other cell types, where chronic infection can be established. In addition, saliva has been shown as a primary route of person-to-person transmission for many viruses. From a clinical perspective, viral infection can lead to several oral manifestations, ranging from common intraoral lesions to tumors. Despite the clinical and biological relevance of initial oral infection, little is known about the mechanism of regulation of the viral life cycle in the oral cavity. Several viruses utilize host epigenetic machinery to promote their own life cycle. Importantly, viral hijacking of host chromatin-modifying enzymes can also lead to the dysregulation of host factors and in the case of oncogenic viruses may ultimately play a role in promoting tumorigenesis. Given the known roles of epigenetic regulation of viral infection, epigenetic-targeted antiviral therapy has been recently explored as a therapeutic option for chronic viral infection. In this review, we highlight three herpesviruses with known roles in oral infection, including herpes simplex virus type 1, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. We focus on the respective oral clinical manifestations of these viruses and their epigenetic regulation, with a specific emphasis on the viral life cycle in the oral epithelium.

Keywords: EBV; HSV-1; KSHV; epigenetic viral gene regulation; herpesviruses; oral infection; polycomb group proteins; viral chromatin.

Figure 1

The oral epithelium and virus challenge: the oral epithelium is often an initial site for viral entry and provides a site for viral replication (1) and subsequent shedding via saliva (2) or spread to other cell types in the underlying connective tissue (3), wherein some viruses, such as the herpesvirus family, can establish chronic infections. Inset: Herpes simplex virus-1 (HSV-1) establishes lifelong latent infection in neurons of the trigeminal ganglion; gammaherpesviruses Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) establish latent infection in B cells. The figure was created with BioRender.

Figure 2

Epigenetic regulation of herpesvirus infections. During latency, lytic viral gene expression is suppressed by the polycomb repressive complex 2 (PRC2). The enzymatic subunit of PRC2 is EZH2, which deposits the repressive histone mark H3K27me3 on the viral chromatin. PRC2-mediated inhibition of lytic gene expression during latency was reported for HSV-1, EBV, and KSHV as well. During the lytic cycle, herpesvirus lytic factors (e.g., HSV-1 VP16; EBV Zta and Rta; KSHV RTA) recruit epigenetic enzymes and chromatin remodeling complexes to the viral promoters, leading to the deposition of activating histone marks (e.g., H3K27ac, H3K4me3) and chromatin changes that activate transcription of lytic viral genes. Note: the illustration of epigenetic factors does not reflect their true biological interactions in every case.