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

Abstract

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.

Effect of CD4+ T cell count on treatment-emergent adverse events among patients with and without HIV receiving immunotherapy for advanced cancer

“… 43 Emerging correlative results from the CITN-12 study indicate that pembrolizumab can reverse the latency of HIV in vivo. 44 This study showed no evidence of HIV clonal expansion despite latency reversal, which provides additional safety data.…”

Selective loss of CD107a TIGIT+ memory HIV-1-specific CD8+ T cells in PLWH over a decade of ART

“…The expression of IRs is a hallmark of Tex (20,22,23) (14), and coexpression of IRs has been associated with HIV-1 disease progression (15,25,29,30,32) and cancer severity (49)(50)(51). ICB has demonstrated promising results in the cancer field (40,41), but the use of ICB as an HIV-1 cure intervention remains unclear (34,(43)(44)(45)(46)(47).…”

“…The expression of IRs is a hallmark of Tex (20,22,23) (14), and co-expression of IRs has been associated with HIV-1 disease progression (15,25,29,30,32) and cancer severity (49–51). ICB has demonstrated promising results in the cancer field (40,41), but the use of ICB as an HIV-1 cure intervention remains unclear (34,43–47). Understanding the dynamics of IRs expression in the context of CD8+ T-cell function in PLWH on ART is essential to guide target identification in developing widely applicable and precise HIV-1 cure immunotherapies based on ICB (48).…”

“…The unprecedented success of the clinical use of ICB in the cancer field (40,41) has prompted the clinical evaluation of ICB in PLWH (42) to boost immunity to reduce or eliminate the viral reservoir. However, the clinical data on the impact of ICB on HIV-1 cure interventions remains unclear (34,(43)(44)(45)(46)(47). In this context, understanding the functional regulation of CD8+ Tex through the dynamics of IRs expression remains elusive in PLWH on ART.…”

The role of latency reversal in HIV cure strategies

“…Antibodies to immune checkpoints, either alone or in combination, have also been shown to reverse HIV latency using both in vitro models and patient‐derived cells 38–40 . Blockade of PD‐1 with the anti‐PD‐1 antibody pembrolizumab was recently shown in a clinical trial to induce expression of both cell‐associated unspliced HIV RNA and plasma RNA in PWH on ART 41 . Antibodies to immune checkpoints can also increase HIV‐specific T‐cell function ex vivo 42 and in vivo; 43 however, whether this increase in HIV‐specific T‐cell function can also clear infected cells in vivo remains unknown.…”