Jones Clinton
Department of Veterinary Pathobiology, Oklahoma State University, College of Veterinary Medicine, Stillwater, Oklahoma, USA.
J Virol. 2025 Apr 15;99(4):e0030325. doi: 10.1128/jvi.00303-25. Epub 2025 Mar 27.
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) shed significantly lower HSV-1 levels compared with age-matched male GR 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.
急性人类α-疱疹病毒1型（HSV-1）感染会导致三叉神经节（TG）、脑干及中枢神经系统其他区域的神经元感染。随后，裂解周期病毒基因表达沉默，一部分神经元在感染中存活下来，并建立终生潜伏状态。与裂解感染不同，潜伏相关转录本（LAT）是潜伏感染神经元中唯一大量表达的病毒基因产物。应激（急性或慢性）、紫外线或热应激会增加人类和小鼠感染模型中潜伏激活的发生率。具有讽刺意味的是，这些不同的激活刺激会激活糖皮质激素受体（GR）。最近的研究表明，GR与Krüppel样因子（KLF），例如KLF4或KLF15，协同反式激活感染细胞蛋白0（ICP0）启动子和顺式调控基序，这些基序可激活ICP4和ICP27启动子活性。GR和KLF4是“先驱转录因子”，即使DNA以异染色质形式存在，它们也能特异性结合DNA；因此，染色质被重塑，转录被激活。相反，一个VP16顺式调控基序被GR和Slug反式激活，但不被KLF家族成员激活。在从潜伏状态激活期间，表达在第229位含有丝氨酸→丙氨酸突变的GR（GR）的雌性小鼠与年龄匹配的雄性GR小鼠或野生型亲代C57BL/6小鼠相比，HSV-1水平显著降低。这些观察结果表明，GR和应激诱导的细胞转录因子在潜伏激活过程中通过激活关键病毒启动子发挥重要作用。GR激活还可能通过损害免疫和炎症反应来增强病毒传播。
