Human immunodeficiency virus 1 (HIV-1) infection is associated with heightened inflammation and excess risk of cardiovascular disease, cancer and other complications. These pathologies persist despite antiretroviral therapy. In two independent cohorts, we found that innate lymphoid cells (ILCs) were depleted in the blood and gut of people with HIV-1, even with effective antiretroviral therapy. ILC depletion was associated with neutrophil infiltration of the gut lamina propria, type 1 interferon activation, increased microbial translocation and natural killer (NK) cell skewing towards an inflammatory state, with chromatin structure and phenotype typical of WNT transcription factor TCF7-dependent memory T cells. Cytokines that are elevated during acute HIV-1 infection reproduced the ILC and NK cell abnormalities ex vivo. These results show that inflammatory cytokines associated with HIV-1 infection irreversibly disrupt ILCs. This results in loss of gut epithelial integrity, microbial translocation and memory NK cells with heightened inflammatory potential, and explains the chronic inflammation in people with HIV-1.

人类免疫缺陷病毒 1 (HIV-1) 感染与炎症加剧以及心血管疾病、癌症和其他并发症的风险增加有关。尽管进行了抗逆转录病毒治疗，这些病症仍然存在。在两个独立的队列中，我们发现，即使采用有效的抗逆转录病毒治疗，HIV-1 感染者的血液和肠道中的先天淋巴细胞 (ILC) 也会被耗尽。 ILC 耗竭与中性粒细胞浸润肠道固有层、1 型干扰素激活、微生物易位增加和自然杀伤 (NK) 细胞偏向炎症状态相关，具有 WNT 转录因子 TCF7 依赖性记忆 T 细胞典型的染色质结构和表型。急性 HIV-1 感染期间升高的细胞因子在体外再现了 ILC 和 NK 细胞异常。这些结果表明，与 HIV-1 感染相关的炎症细胞因子不可逆地破坏 ILC。这导致肠道上皮完整性丧失、微生物易位和记忆性 NK 细胞的炎症潜力增强，并解释了 HIV-1 感染者的慢性炎症。