Chronic, low-grade, systemic, and mucosal inflammation correlates with increased morbidity and poor clinical outcomes among patients living with human immunodeficiency virus (HIV). These long-term complications are linked to the disruption of gastrointestinal (GI) tract epithelial barrier integrity and subsequent microbial translocation. However, the mechanisms responsible for these downstream effects of infection are unknown. Here, we demonstrate that during the disruption of the GI tract and increased microbial translocation, we find inflammatory cytokines (e.g., interferon gamma [IFN-γ] and tumor necrosis factor alpha [TNF-α]) produced by innate lymphoid cells (ILCs) located in the colon secondary to simian immunodeficiency virus (SIV) infection. To do this, we used viably cryopreserved colon cells from SIV-infected and uninfected rhesus macaque monkeys and determined the make-up of the ILC subpopulations and the cytokines they expressed constitutively. Our studies revealed that the interleukin-22 (IL-22)/IL-17-producing ILCS was not altered during SIV infection. However, the percentage of IFN-γ+ ILCs in infected colons was 5- to 10-fold higher than that in uninfected colons. ILCs from infected tissue that produced IFN-γ also expressed TNF-α and IL-22. The coexpression of inflammatory cytokines with IL-22 is linked to the ability of ILCs to coexpress T-bet and RORγT/Ahr. The expression of IFN-γ/TNF-α by ILCs and NK cells combined likely triggers a pathway that contributes to chronic mucosal inflammation, GI barrier breakdown, and microbial translocation within the context of SIV/HIV infection.IMPORTANCE There is a slow yet significant uptick in systemic inflammation secondary to HIV infection that has long-term consequences for the infected host. The systemic inflammation most likely occurs as a consequence of the disruption of the gut epithelial barrier, leading to the translocation of gut microbial products. This disruption may result from mucosal inflammation. Here, we show in an animal model of HIV that chronic SIV-infected gut contains innate lymphoid cells producing inflammatory cytokines.

中文翻译：

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感染猿猴免疫缺陷病毒的恒河猴结肠中存在 I 组和 III 组炎症先天淋巴细胞。


人类免疫缺陷病毒 (HIV) 感染者的慢性、低度、全身性和粘膜炎症与发病率增加和临床结果不佳相关。这些长期并发症与胃肠道上皮屏障完整性的破坏以及随后的微生物易位有关。然而，造成这些感染下游效应的机制尚不清楚。在这里，我们证明，在胃肠道破坏和微生物易位增加的过程中，我们发现先天淋巴细胞 (ILC) 产生炎症细胞因子（例如干扰素 γ [IFN-γ] 和肿瘤坏死因子 α [TNF-α]）位于继发于猿猴免疫缺陷病毒（SIV）感染的结肠中。为此，我们使用了来自 SIV 感染和未感染的恒河猴的冷冻结肠细胞，并确定了 ILC 亚群的组成及其组成型表达的细胞因子。我们的研究表明，在 SIV 感染期间，产生白细胞介素 22 (IL-22)/IL-17 的 ILCS 并未发生改变。然而，感染结肠中 IFN-γ+ ILC 的百分比比未感染结肠中高 5 至 10 倍。来自感染组织的 ILC 产生 IFN-γ，也表达 TNF-α 和 IL-22。炎症细胞因子与 IL-22 的共表达与 ILC 共表达 T-bet 和 RORγT/Ahr 的能力有关。 ILC 和 NK 细胞联合表达 IFN-γ/TNF-α 可能会触发一条途径，导致 SIV/HIV 感染背景下的慢性粘膜炎症、胃肠道屏障破坏和微生物易位。 HIV 感染继发的全身炎症加剧，对受感染宿主产生长期后果。 全身炎症很可能是由于肠道上皮屏障破坏导致肠道微生物产物易位而发生的。这种破坏可能是由粘膜炎症引起的。在这里，我们在 HIV 动物模型中证明，慢性 SIV 感染的肠道含有产生炎症细胞因子的先天淋巴细胞。