Abstract
BACKGROUND: Immunotherapeutic strategies combining Immune checkpoint blockade (ICB) and therapeutic T-cell vaccination hold promise to enhance HIV-1 remission in people with HIV (PWH). While T-cell vaccination alone has shown limited efficacy, ICB may potentiate vaccine-induced T-cell responses. We investigate the functional impact of ICB on vaccine-induced HIV-1-specific CD8(+) T-cell responses using relevant samples from PWH receiving early ART and T-cell vaccination. METHODS: We conducted comparative laboratory studies on PD-1 and TIM-3 blockade using biological samples from PWH on early ART and T-cell vaccination (Etvac), or without vaccination (Et) from the BCN01 trial, a phase I non-randomised, multicenter therapeutic HIV-1 vaccine study. Also, we included samples from PWH receiving ART during chronic infection stages (Chro). We assessed and characterised vaccine-induced and HIV-1-specific CD8(+) T-cell responses using in vitro peptide stimulation, flow cytometry and multiplex assays. We also investigated correlates of response to ICB. FINDINGS: PD-1 blockade significantly increased vaccine-induced HIV-1-specific CD8(+) T cell responses in the Etvac group, primarily absent prior vaccination, with no effect from TIM-3 blockade. No effect was found in the Et group for any of the tested conditions, while Chro under PD-1 or PD-1/TIM-3 blockade elicited an increase in HIV-1-specific CD8(+) T cells. Differentially, vaccine-induced HIV-1-specific CD8(+) T cells in response to PD-1 blockade co-express functional markers, sharing a unique profile of soluble molecules. Furthermore, PD-1 expression on CD8(+) T cells correlated with in vitro response to PD-1 blockade in Etvac, suggesting its potential as a biomarker in vaccine studies. INTERPRETATION: PD-1 blockade enhances functional vaccine-induced HIV-1-specific CD8(+) T-cell responses in PWH during early treatment, supporting further clinical investigation into combining ICB to improve therapeutic T-cell vaccine efficacy in PWH. FUNDING: This research was partially supported by grants from the National Health Institute Carlos III (PI17/00164), Merck Sharp & Dohme LLC (MSD LKR 155762), a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and the Catalan Government with the European Social Fund (AGAUR-FI_B 00582 and 2021 SGR 00452).