Impacts of immune checkpoint inhibitors use on the HIV reservoir are linked to provirus sequences but not integration sites

Antibodies to programmed cell death 1 (PD-1), Programmed death-ligand 1 (PDL-1) and Cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) can revert HIV latency and enhance anti-HIV cytotoxic response but their impact on HIV proviral sequences and integration landscape in people with HIV (PWH) remain to be studied. Two PWH treated with PD-1/PDL-1 and one with PD-1/CTLA4 were studied among the ANRS-CO-24 OncoVIHAC cohort study. Matched integration site and proviral sequencing were performed pre- and post-treatment. Immune checkpoint inhibitors (ICI) were not associated with significant changes in total cell-associated HIV-DNA, nor significant changes in genomic or epigenetic features of integration sites. ICIs were associated with a lesser proportion of proviruses with pol frameshifts for all regimen, with the PD-1 and PD-1/CTLA4 patients also experiencing a higher proportion of proviral sequences harboring gag frameshifts and a higher number of STOP codons, consistent with a gag-driven immune clearance. ICI use were also associated with a limited reduction in the HIV-reservoir diversity. Finally, the patient with a PD-1/CTLA4 treatment exhibited the loss of an HIV-clone in the NIN-oncogene representing 17% of all his pre-treatment sequences. Despite stable levels of cell-associated HIV DNA, ICI treatment can lead to modest changes in proviral sequences landscapes.