The mechanisms underlying rapid elimination of herpes simplex virus-2 (HSV-2) in the human genital tract despite low CD8+ and CD4+ tissue-resident T cell (Trm cell) density are unknown. We analyzed shedding episodes during chronic HSV-2 infection: viral clearance always predominated within 24 hours of detection even when viral load exceeded 107 HSV DNA copies; surges in granzyme B and IFN-γ occurred within the early hours after reactivation and correlated with local viral load. We next developed an agent-based mathematical model of an HSV-2 genital ulcer to integrate mechanistic observations of Trm cells in in situ proliferation, trafficking, cytolytic effects, and cytokine alarm signaling from murine studies with viral kinetics, histopathology, and lesion size data from humans. A sufficiently high density of HSV-2-specific Trm cells predicted rapid elimination of infected cells, but our data suggest that such Trm cell densities are relatively uncommon in infected tissues. At lower, more commonly observed Trm cell densities, Trm cells must initiate a rapidly diffusing, polyfunctional cytokine response with activation of bystander T cells in order to eliminate a majority of infected cells and eradicate briskly spreading HSV-2 infection.

中文翻译：

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组织驻留 T 细胞衍生的细胞因子可消除单纯疱疹病毒 2 感染的细胞。

尽管 CD8+ 和 CD4+ 组织驻留 T 细胞（Trm 细胞）密度较低，但在人类生殖道中快速消除单纯疱疹病毒 2 (HSV-2) 的机制尚不清楚。我们分析了慢性 HSV-2 感染期间的排毒事件：即使病毒载量超过 107 个 HSV DNA 拷贝，病毒清除也总是在检测后 24 小时内占主导地位；颗粒酶 B 和 IFN-γ 的激增发生在重新激活后的早期，并与局部病毒载量相关。接下来，我们开发了一种基于药物的 HSV-2 生殖器溃疡数学模型，以整合 Trm 细胞在原位增殖、运输、细胞溶解作用和小鼠研究中的细胞因子警报信号与病毒动力学、组织病理学和病变大小数据中的机械观察来自人类。足够高密度的 HSV-2 特异性 Trm 细胞预示着感染细胞的快速消除，但我们的数据表明这种 Trm 细胞密度在感染组织中相对不常见。在较低的、更常见的 Trm 细胞密度下，Trm 细胞必须通过激活旁观者 T 细胞来启动快速扩散的多功能细胞因子反应，以消除大部分受感染的细胞并根除快速传播的 HSV-2 感染。