Department of Tropical Medicine.
Hawaii Center for AIDS.
AIDS. 2020 Aug 1;34(10):1451-1460. doi: 10.1097/QAD.0000000000002557.
The aim of this study was to examine the relationship between gut microbial communities in HIV-infected individuals on suppressive antiretroviral therapy (cART), and the peripheral HIV-Gag-specific CD8 T-cell responses before and after ex-vivo immune checkpoint blockade (ICB).
Thirty-four HIV-seropositive, 10 HIV-seronegative and 12 HIV-seropositive receiving faecal microbiota transplant (FMT) participants were included. Gut microbial communities, peripheral and gut associated negative checkpoint receptors (NCRs) and peripheral effector functions were assessed.
Bacterial 16s rRNA sequencing for gut microbiome study and flow-based assays for peripheral and gut NCR and their cognate ligand expression, including peripheral HIV-Gag-specific CD8 T-cell responses before and after ex-vivo anti-PD-L1 and anti-TIGIT ICB were performed.
Fusobacteria abundance was significantly higher in HIV-infected donors compared to uninfected controls. In HIV-infected participants receiving Fusobacteria-free FMT, Fusobacteria persisted up to 24 weeks in stool post FMT. PD-1 TIGIT and their ligands were expanded in mucosal vs. peripheral T cells and dendritic cells, respectively. PD-L1 and TIGIT blockade significantly increased the magnitude of peripheral anti-HIV-Gag-specific CD8 T-cell responses. Higher gut Fusobacteria abundance was associated with lower magnitude of peripheral IFN-γ+ HIV-Gag-specific CD8 T-cell responses following ICB.
The gut colonization of Fusobacteria in HIV infection is persistent and may influence anti-HIV T-cell immunity to PD-1 or TIGIT blockade. Strategies modulating Fusobacteria colonization may elicit a favourable mucosal immune landscape to enhance the efficacy of ICB for HIV cure.
本研究旨在探讨接受抑制性抗逆转录病毒疗法（cART）的 HIV 感染者肠道微生物群落与外周 HIV-Gag 特异性 CD8 T 细胞反应之间的关系，并分析免疫检查点阻断（ICB）前后的关系。
本研究纳入了 34 名 HIV 阳性、10 名 HIV 阴性和 12 名接受粪便微生物群移植（FMT）的 HIV 阳性参与者。评估了肠道微生物群落、外周和肠道相关负检查点受体（NCR）以及外周效应功能。
进行了肠道微生物组研究的细菌 16s rRNA 测序以及外周和肠道 NCR 及其同源配体表达的流式细胞术检测，包括外周 HIV-Gag 特异性 CD8 T 细胞反应在接受 ex vivo 抗 PD-L1 和抗 TIGIT ICB 前后的反应。
与未感染对照组相比，HIV 感染者供体的梭菌丰度显著升高。在接受无梭菌 FMT 的 HIV 感染者中，Fusobacteria 在 FMT 后粪便中持续存在长达 24 周。PD-1 TIGIT 及其配体在外周 T 细胞和树突状细胞中分别扩增。PD-L1 和 TIGIT 阻断显著增加了外周抗 HIV-Gag 特异性 CD8 T 细胞反应的幅度。肠道 Fusobacteria 丰度较高与 ICB 后外周 IFN-γ+ HIV-Gag 特异性 CD8 T 细胞反应幅度较低相关。
HIV 感染中 Fusobacteria 的肠道定植是持久的，可能影响抗 HIV T 细胞免疫对 PD-1 或 TIGIT 阻断的反应。调节 Fusobacteria 定植的策略可能会引发有利的黏膜免疫景观，从而提高 ICB 治疗 HIV 治愈的疗效。
