Human alpha-herpesvirus 1 (HSV-1) viral replication and reactivation from latency are expedited by the glucocorticoid receptor.

Abstract

Acute human alpha-herpesvirus 1 (HSV-1) infection leads to infection of neurons within trigeminal ganglia (TG), brainstem, and other regions of the central nervous system. Lytic cycle viral gene expression is subsequently silenced, a subset of neurons survive infection, and life-long latency is established. In contrast to lytic infection, the latency-associated transcript (LAT) is the only viral gene product abundantly expressed in latently infected neurons. Stress (acute or chronic), UV light, or heat stress increases the incidence of reactivation from latency in humans and mouse models of infection. Ironically, these divergent reactivation stimuli activate the glucocorticoid receptor (GR). Recent studies revealed GR and Krüppel-like factors (KLF), KLF4 or KLF15 for example, cooperatively transactivate the infected cell protein 0 (ICP0) promoter and cis-regulatory motifs that activate ICP4 and ICP27 promoter activity. GR and KLF4 are "pioneer transcription factors" that specifically bind DNA even when it exists as heterochromatin; consequently, chromatin is remodeled, and transcription is activated. Conversely, a VP16 cis-regulatory motif is transactivated by GR and Slug but not KLF family members. Female mice that express a GR containing a serine → alanine mutation at position 229 (GR^S229A) shed significantly lower HSV-1 levels compared with age-matched male GR^S229A mice or wild-type parental C57BL/6 mice during reactivation from latency. These observations imply GR and stress-induced cellular transcription factors play an important role during reactivation from latency by activating key viral promoters. GR activation may also enhance virus spread by impairing immune and inflammatory responses.