Anti–PD-1 Therapy Reverses HIV Latency in Patients with HIV and Cancer

Antiretroviral therapy (ART) has demonstrated success in patients living with HIV; however, latent HIV represents a barrier to fully curing HIV. Reversal of HIV latency through increasing HIV transcription and viral production could thus allow for immune recognition and elimination of infected cells, but no latency-reversing agents to date have demonstrated consistent effects. PD-1 has been shown to be upregulated in people living with HIV and is preferentially expressed on latently infected cells in both blood and tissue. Therefore, Uldrick and colleagues investigated if targeting PD-1 through the use of anti–PD-1 antibodies administered every 3 weeks would reverse latency in 32 patients with both HIV and cancer on ART. These patients had a wide range of cancer types in addition to well-controlled HIV at baseline. Administration of pembrolizumab (anti–PD-1 antibody) therapy demonstrated an increase in unspliced HIV RNA after day 8 of treatment (1 infusion of pembrolizumab), while unspliced HIV DNA decreased 1 day after infusion leading to an increase in the HIV unspliced RNA:DNA ratio on day 8. Those who completed 6 cycles of pembrolizumab treatment showed an increase in inducible HIV transcription as well as the frequency of CD4⁺ T cells with inducible virus as evaluated by the tat/rev limiting dilution assay. Additionally, using HIV single-genome sequencing from a participant with low plasma HIV RNA concentrations after anti–PD-1 therapy and continued adherence to ART, phylogenetic analyses were performed and indicated no evident clonal expansion of HIV-infected cells. This study demonstrates a clear effect of a single dose of anti–PD-1 therapy on reversing HIV latency and rationally supports use of this with other therapies to reduce the HIV reservoir. However, further studies are needed to determine ways to decrease toxicity and immune-related adverse events as well as to determine the generalizability of the results to a population without cancer.

Uldrick TS, Adams SV, Fromentin R, Roche M, Fling SP, Gonçalves PH, et al. Pembrolizumab induces HIV latency reversal in people living with HIV and cancer on antiretroviral therapy. Sci Transl Med 2022;14:eabl3836.

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