Background:
Antiretroviral therapy (ART) is not curative and HIV patients continue to present with co-morbidities including cancer. Persistence of HIV in latently-infected CD4 T cells remains a major impediment to eradication. These cells express high levels of inhibitory receptor PD-1, which is associated with immune dysfunction in both HIV infection and cancer. Inhibitors that target PD-1 have been successful against cancers and have proven to be safe/can effectively target the HIV reservoir in cancer patients living with HIV. The mechanisms associated with HIV reservoir decay in these patients remain unknown.
Methods:
Immune responses from 30 cancer patients living with HIV who received Pembrolizumab monoclonal antibody against PD-1 every 3 weeks for up to 2 years (Cancer Immunotherapy Network-12 trial) were profiled using an integrated multiomic approach. Plasma and PBMC responses (assessed using flow cytometry and single-cell/bulk RNA-sequencing) were measured at baseline, 24 hours, and 1 week following therapy and at the end of treatment (EOT) to identify molecular and cellular mechanisms associated with decay of the HIV reservoir.
Results:
Anti-PD-1 therapy was associated with a further decrease in HIV reservoir in patients that had reduced HIV reservoir at baseline; and increase in HIV RNA within 1 week (P < 0.05) that remained significant at EOT (P < 0.05). Our multiomic analyses shows that anti-PD-1 therapy leads to a rapid increase (within 24h) in effector CD8 T cell function gene expression concomitant with increased plasma viral RNA, and reduced TGF-bsignaling (GSEA; P < 0.05). Higher frequencies of classical monocytes with augmented anti-viral functions and increased transcription of interferon-stimulated genes (IRF1, 7, 9 and higher plasma IFN-b/g), chemokine secretion (CXCL9, 10), restriction factors (TRIM21, 22), and TLR signaling (TLR4 and high plasma IL-6) were also observed 24h after therapy initiation. Importantly, this early monocyte specific antiviral signature persisted only in the 8 participants that maintain reduced HIV reservoir levels at EOT.
Conclusions:
Our data demonstrate that anti-PD-1 therapy rapidly induces sustained antiviral innate responses as early as day 1 post treatment initiation that can lead to long-term reservoir reduction by limiting infection of new target cells and priming effector HIV specific T cell responses. Our findings pave the way for mechanism-based therapeutic opportunities that can help eradicate HIV.