Objectives: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).Design: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.Methods: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.Results: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.Conclusion: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.
Bibliographical noteFunding Information:
National Institute of General Medical Sciences (NIGMS) 1U54GM104944-01A1 (I.N.S.), National Institutes of Health award numbers NIH/NIDDK RO1DK112254 and NIH/NIDA 1DP13A037979 (N.R.K.) and National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) (M.S.) and University of Washington Center for AIDS Research funded by the National Institutes of Health AI027757.
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- immune checkpoint blockade
- programmed death-ligand 1