HIV-1 病毒 DNA/RNA 与免疫代谢：在 HIV-1 感染者中对慢性免疫激活和炎症的贡献。

HIV-1-DNA/RNA and immunometabolism in monocytes: contribution to the chronic immune activation and inflammation in people with HIV-1.

机构信息

Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Institute of Biomedicine of Seville/Virgen del Rocio University Hospital/CSIC/University of Seville, Spain.

Department of Clinical Biochemistry, Virgen del Rocío University Hospital, Seville, Spain.

出版信息

EBioMedicine. 2024 Oct;108:105338. doi: 10.1016/j.ebiom.2024.105338. Epub 2024 Sep 11.

DOI:10.1016/j.ebiom.2024.105338

PMID:39265504

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11416497/

Abstract

BACKGROUND

Among people living with HIV-1 (PHIV), immunological non-responders (INR) experience incomplete immune recovery despite suppressive antiretroviral treatment (ART), facing more severe non-AIDS events than immunological responders (IR) due to higher chronic immune activation and inflammation (cIA/I). We analyzed the HIV-1 reservoir and immunometabolism in monocytes as a source of cIA/I.

METHODS

Cross-sectional study in which 110 participants were enrolled: 25 treatment-naïve; 35 INR; 40 IR; and 10 healthy controls. Cell-associated HIV-1-DNA (HIV-DNA) and -RNA (HIV-RNA) were measured in FACS-isolated monocytes using digital droplet PCR. Intact, 5' deleted, and 3' deleted proviruses were quantified by the intact proviral DNA assay. Systemic inflammation, monocyte immunophenotype, and immunometabolism were characterized by immunoassays, flow cytometry, and real-time cellular bioenergetics measurements, respectively.

FINDINGS

Monocytes from INR harbor higher HIV-RNA and HIV-DNA levels than IR. HIV-RNA was found in 14/21 treatment-naïve [2512 copies/10 TBP (331-4666)], 17/33 INR [240 (148-589)], and 15/28 IR [144 (15-309)], correlating directly with sCD163, IP-10, GLUT1 cells and glucose uptake, and inversely with the CD4/CD8 ratio. HIV-DNA was identified in all participants with detectable HIV-RNA, with intact provirus in 9/12 treatment-naïve [13 copies/10 monocytes (7-44)], 8/14 INR [46 (18-67)], and 9/13 IR [9 (7-24)]. INR presented glucose metabolism alterations and mitochondrial impairment; decreased coupling efficiency and BHI, and increased mitochondrial dysfunction inversely correlating with the CD4/CD8 ratio.

INTERPRETATION

HIV-RNA, more than HIV-DNA, in monocytes and their altered metabolism are factors associated with the higher cIA/I that characterize INR.

FUNDING

This work was supported by the European Regional Development Fund, ISCIII, grant PI20/01646. Other funding sources: Instituto de Salud Carlos III through the Subprogram Miguel Servet (CP19/00159) to AGV, PFIS contracts (FI19/00304) to EMM, (FI21/00165) to ASA, and (FI19/00083) to CGC, and a mobility grant (MV21/00103) to EMM, from the Ministerio de Ciencia e Innovación, Spain. AJM was granted by a CSL Centenary Award.

摘要

背景

在感染 HIV-1（PHIV）的人群中，免疫无应答者（INR）尽管接受了抑制性抗逆转录病毒治疗（ART），但仍未能完全恢复免疫，由于慢性免疫激活和炎症（cIA/I）水平较高，他们面临着比免疫应答者（IR）更严重的非艾滋病事件。我们分析了 HIV-1 储库和作为 cIA/I 来源的单核细胞中的免疫代谢。

方法

这是一项横断面研究，共纳入 110 名参与者：25 名未经治疗的患者；35 名 INR；40 名 IR；和 10 名健康对照者。使用数字液滴 PCR 法在 FACS 分离的单核细胞中测量细胞相关 HIV-1-DNA（HIV-DNA）和 -RNA（HIV-RNA）。通过完整原病毒 DNA 测定法定量完整、5'缺失和 3'缺失原病毒。通过免疫测定法、流式细胞术和实时细胞生物能量学测量分别对系统性炎症、单核细胞免疫表型和免疫代谢进行了特征描述。

结果

INR 的单核细胞中 HIV-RNA 和 HIV-DNA 水平高于 IR。在 21 名未经治疗的患者[2512 拷贝/10TBP（331-4666）]、33 名 INR[240（148-589）]和 28 名 IR[144（15-309）]中发现了 HIV-RNA，与 sCD163、IP-10、GLUT1 细胞和葡萄糖摄取直接相关，与 CD4/CD8 比值呈负相关。所有可检测到 HIV-RNA 的患者均检测到 HIV-DNA，其中 12 名未经治疗的患者中有 9 名（13 拷贝/10 个单核细胞（7-44））、14 名 INR[46（18-67）]和 13 名 IR[9（7-24）]中有完整原病毒。INR 表现出葡萄糖代谢改变和线粒体损伤；降低了耦合效率和 BHI，并增加了线粒体功能障碍，与 CD4/CD8 比值呈负相关。

结论

与单核细胞中更高的 cIA/I 相关的因素是 HIV-RNA，而不是 HIV-DNA，以及其改变的代谢。

资金

这项工作得到了欧洲区域发展基金、ISCIII 的支持，资助项目为 PI20/01646。其他资金来源：西班牙卡洛斯三世健康研究所通过 Miguel Servet 子计划（CP19/00159）向 AGV、PFIS 合同（FI19/00304）向 EMM、（FI21/00165）向 ASA 和（FI19/00083）向 CGC 提供资金，并向 EMM 提供了一项流动性补助金（MV21/00103），来自西班牙科学和创新部。AJM 获得了 CSL 百年纪念奖。