Impaired glucocorticoid receptor function attenuates herpes simplex virus 1 production during explant-induced reactivation from latency in female mice.

Following acute infection, sensory neurons in trigeminal ganglia (TG) are important sites for the life-long latency of human alpha-herpes virus 1 (HSV-1). Acute or chronic stress in humans correlates with increased reactivation from latency, which can lead to recurrent HSV-1 disease, for example, herpes labialis, herpes stromal keratitis, and encephalitis. The glucocorticoid receptor (GR) and the synthetic corticosteroid dexamethasone stimulate key viral transcriptional cis-regulatory modules, viral replication, and explant-induced reactivation from latency. Conversely, a GR-specific antagonist impairs explant-induced reactivation and viral replication. Based on these observations, we hypothesize that GR transcriptional activity enhances reactivation from latency. To test this hypothesis, the HSV-1 latency-reactivation cycle was examined in mice containing a serine 229 to alanine mutation in GR (GR S229A ) because phosphorylation of GR serine 229 is crucial for GR-mediated transcription. Virus yields from cornea and conjunctiva of infected GR S229A mice ceased before wild-type (wt) mice, consistent with reduced viral replication in kidney cells from GR S229A mice. However, viral DNA levels in TG were not significantly different during latency and similar numbers of TG neurons express GR in GR S229A and WT mice. Strikingly, HSV-1 viral titers during explant-induced reactivation were significantly reduced in female GR S229A mice versus male GR S229A mice or wt mice. The number of VP16 + TG neurons in female GR S229A mice was significantly lower than in male GR S229A or wt mice (males and females) during the early stages of explant-induced reactivation. Collectively, these studies revealed that GR phosphorylation of serine 229 is more important in GR S229A female mice versus males during explant-induced reactivation from latency. IMPORTANCE A correlation exists between stress and increased episodes of human alpha-herpes virus 1 reactivation from latency. Stress increases corticosteroid levels; consequently, the glucocorticoid receptor (GR) is activated. Recent studies concluded that a GR agonist, but not an antagonist, accelerates productive infection and reactivation from latency. Furthermore, GR and certain stress-induced transcription factors cooperatively transactivate promoters that drive the expression of infected cell protein 0 (ICP0), ICP4, and VP16. This study revealed female mice expressing a GR containing a serine to alanine mutation at position 229 (GR S229A ) shed significantly lower levels of infectious virus during explant-induced reactivation compared to male GR S229A or wild-type parental C57BL/6 mice. Furthermore, female GR S229A mice contained fewer VP16 + TG neurons compared to male GR S229A mice or wild-type mice during the early stages of explant-induced reactivation from latency. Collectively, these studies revealed that GR transcriptional activity has female-specific effects, whereas male mice can compensate for the loss of GR transcriptional activation.