Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, USA.
Nat Immunol. 2020 Mar;21(3):274-286. doi: 10.1038/s41590-020-0593-9. Epub 2020 Feb 17.
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）感染与炎症增强以及心血管疾病、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，但这些病理仍然存在。在两个独立的队列中，我们发现 HIV-1 患者的血液和肠道中的固有淋巴细胞（ILC）耗竭，即使接受有效的抗逆转录病毒治疗也是如此。ILC 耗竭与肠道固有层中性粒细胞浸润、I 型干扰素激活、微生物易位增加以及自然杀伤（NK）细胞向炎症状态倾斜有关，其染色质结构和表型与 WNT 转录因子 TCF7 依赖性记忆 T 细胞相似。在急性 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转地破坏了 ILC。这导致肠道上皮完整性丧失、微生物易位和具有更高炎症潜力的记忆 NK 细胞丢失，并解释了 HIV-1 患者的慢性炎症。
