Pembrolizumab induces HIV latency reversal in people living with HIV and cancer on antiretroviral therapy

In people living with HIV (PLWH) on antiretroviral therapy (ART), virus persists in a latent form where there is minimal transcription or protein expression. Latently infected cells are a major barrier to curing HIV. Increasing HIV transcription and viral production in latently infected cells could facilitate immune recognition and reduce the pool of infected cells that persist on ART. Given that programmed cell death protein 1 (PD-1) expressing CD4(+) T cells are preferentially infected with HIV in PLWH on ART, we aimed to determine whether administration of antibodies targeting PD-1 would reverse HIV latency in vivo. We therefore evaluated the impact of intravenous administration of pembrolizumab every 3 weeks on HIV latency in 32 PLWH and cancer on ART. After the first infusion of anti-PD-1, we observed a median 1.32-fold increase in unspliced HIV RNA and 1.61-fold increase in unspliced RNA:DNA ratio in sorted blood CD4(+) T cells compared to baseline. We also observed a 1.65-fold increase in plasma HIV RNA. The frequency of CD4(+) T cells with inducible virus evaluated using the tat/rev limiting dilution assay was higher after 6 cycles compared to baseline. Phylogenetic analyses of HIV env sequences in a participant who developed low concentrations of HIV viremia after 6 cycles of pembrolizumab did not demonstrate clonal expansion of HIV-infected cells. These data are consistent with anti-PD-1 being able to reverse HIV latency in vivo and support the rationale for combining anti-PD-1 with other interventions to reduce the HIV reservoir.

Automated summary

This study aimed to evaluate the effect of anti-PD-1 antibodies on reversing HIV latency. The results showed that administration of anti-PD-1 antibodies increased the levels of unspliced HIV RNA and the RNA:DNA ratio in CD4(+) T cells. There was also an increase in the frequency of CD4(+) T cells with inducible virus. The study suggests that combining anti-PD-1 with other interventions may help reduce the HIV reservoir.