Herpesvirus prevalence and methylation status in ganglia of the human head and neck

Abstract

The neurotropic human alphaherpesviruses, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and varicella-zoster virus (VZV), are latent in a majority of the adult population. These viruses can reactivate to cause many diseases (e.g. herpes labialis, shingles) and sometimes unusual clinical sitespecific neurological syndromes ranging from neuralgia to deadly encephalitis. Although the trigeminal ganglion has been thought to be the main site of reactivation, additional sensory and autonomic ganglia contain viral genomes. A comprehensive study of these additional sites of latency and their respective viral burden is needed to understand the full spectrum of latency and possible sites of viral reactivation in humans. While animal models of HSV provide some insight into the pathogenesis of herpesvirus infections, they do not provide information about the prevalence and characteristics of these viruses in their natural host. The overall goal of this study was to elucidate the distribution of the neurotropic human herpesviruses and to determine whether ganglionic positivity at one site in the head and neck correlated with virus presence in ipsilateral and/or contralateral sites. By using formalin-fixed tissue from human cadavers, we were able to: 1) investigate the frequency and correlation of genomes in 8 ganglia on each side of the head and neck, and 2) determine whether latent virus exists in a methylated state. From these studies, we now have a more complete characterization of latency patterns in the human head and neck. This thorough comparison among 16 ganglia around the head and neck provided a more comprehensive perspective of the pattern of latency and by extrapolation, of sites of possible reactivation. The results of these studies suggest that HSV-1 and VZV (but not HSV-2) are independently distributed among ganglia of the human head and neck and that DNA methylation of the HSV-1 genome is not a likely epigenetic mechanism in latently infected human ganglia. An expanded knowledge of latency sites, prevalence of latency, and epigenetic mechanisms of latent viruses in the head and neck may provide insight into the pathogenesis of herpesvirus infection in unusual sites. Such knowledge may also be used to develop approaches to reduce or prevent reactivation or to ameliorate the effects of herpesvirus infections of the head and neck.