Antiretroviral therapy (ART) suppresses HIV but does not eliminate the latent viral reservoir, which persists in programmed cell death protein 1 (PD-1)-expressing CD4+ T cells. Anti-PD-1 therapies have reduced the HIV reservoir in people living with HIV (PLWH) and cancer; however, the individuals who benefit and the mechanisms driving reservoir reduction remain unclear. We performed a prespecified exploratory, longitudinal multiomic profiling of 30 PLWH (29 males and one female) with cancer in the phase 1 CITN-12 clinical trial, in which pembrolizumab was evaluated for safety and preliminary antitumor activity. The therapy was generally well tolerated, with most adverse events graded 1-2 and objective antitumor response observed in five participants (one complete response and four partial responses). Within 24 hours of treatment, we observed an expansion of proliferating HIV-specific effector CD8+ T cells and a decline in plasma TGFβ. Furthermore, among the 14 participants tracked to the end of treatment (ranging from 44 to 315 days after therapy initiation), nine display early induction and sustained expression of interferon-stimulated genes (ISGs), antiviral restriction factors and Toll-like receptor (TLR) signaling and a reduction in the HIV reservoir. Mapping these transcriptomic signatures across more than 1,000 public single-cell RNA sequencing datasets reveals that anti-PD-1-induced programs are present in subsets of across subsets of disease states, indicating that some people already display a heightened antiviral state. Together, these findings define immune pathways that help identify PLWH most likely to experience reservoir decay with anti-PD-1 therapy and suggest that sustained ISG activation may contribute to reservoir reduction and prevention of viral rebound upon ART interruption. ClinicalTrials.gov registration: NCT02595866 .
© 2026. The Author(s).