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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\n            <jats:sup>S229A<\/jats:sup>\n            ) because phosphorylation of GR serine 229 is crucial for GR-mediated transcription. Virus yields from cornea and conjunctiva of infected GR\n            <jats:sup>S229A<\/jats:sup>\n            mice ceased before wild-type (wt) mice, consistent with reduced viral replication in kidney cells from GR\n            <jats:sup>S229A<\/jats:sup>\n            mice. However, viral DNA levels in TG were not significantly different during latency and similar numbers of TG neurons express GR in GR\n            <jats:sup>S229A<\/jats:sup>\n            and WT mice. Strikingly, HSV-1 viral titers during explant-induced reactivation were significantly reduced in female GR\n            <jats:sup>S229A<\/jats:sup>\n            mice versus male GR\n            <jats:sup>S229A<\/jats:sup>\n            mice or wt mice. The number of VP16 + TG neurons in female GR\n            <jats:sup>S229A<\/jats:sup>\n            mice was significantly lower than in male GR\n            <jats:sup>S229A<\/jats:sup>\n            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\n            <jats:sup>S229A<\/jats:sup>\n            female mice versus males during explant-induced reactivation from latency.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              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\n              <jats:sup>S229A<\/jats:sup>\n              ) shed significantly lower levels of infectious virus during explant-induced reactivation compared to male GR\n              <jats:sup>S229A<\/jats:sup>\n              or wild-type parental C57BL\/6 mice. Furthermore, female GR\n              <jats:sup>S229A<\/jats:sup>\n              mice contained fewer VP16 + TG neurons compared to male GR\n              <jats:sup>S229A<\/jats:sup>\n              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.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.01305-23","type":"journal-article","created":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T13:02:38Z","timestamp":1697115758000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["Impaired glucocorticoid receptor function attenuates herpes simplex virus 1 production during explant-induced reactivation from latency in female mice"],"prefix":"10.1128","volume":"97","author":[{"given":"Kelly S.","family":"Harrison","sequence":"first","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University , Stillwater, Oklahoma, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishani","family":"Wijesekera","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University , Stillwater, Oklahoma, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia G. 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