Immune checkpoint blockade (ICB) is highly effective for the management of some malignancies and can potentially perturb HIV persistence in people living with HIV (PLWH) on antiretroviral therapy (ART) by enhancing HIV-specific CD8+ T cells and/or reversing HIV latency. We established a prospective cohort of PLWH on ART with malignancy who received any ICB and quantified immunological and virological changes in three participants.
Blood was collected prior to and following the first 4 cycles of ICB at day-1,+1 and +7. We quantified cell associated (CA) unspliced (US) RNA and HIV DNA from peripheral blood CD4+ T cells, frequency of cells with inducible multiply spliced (MS) HIV RNA by the Tat/rev Induced Limiting Dilution Assay (TILDA) and HIV RNA in plasma by single copy assay (SCA). Gag specific immune responses were measured by intracellular cytokine staining (ICS) for IFN-γ, TNF-α, and CD107a in T-cell subsets defined by expression of CD45RA and CCR7.
Participant (P) 1 received avelumab (anti-PD-L1) 2 weekly for chest wall Merkel cell carcinoma. P2 and P3 received ipilimumab (anti-CTLA4) and nivolumab (anti-PD1) 3 weekly for metastatic melanoma. P1 demonstrated partial response to ICB, before relapse and progression of disease. P2 had disease progression on ICB and died before study completion. P3 responded to ICB and remains on maintenance anti-PD-1.
An increase in CA-US RNA following each infusion was noted in all 3 participants (Fig1 A,B). There was an increase in the mean fold change in CA-US RNA from cycle 1 to 4 of 1.3, 3.1, 6.8 and 8.6 respectively. No consistent changes in HIV DNA were noted in any participants. P3 had an increase in plasma viremia from a baseline of 4 c/mL to 16 and 8 c/ml following cycle 2 and 3 respectively, and a 33% reduction in inducible MS RNA as measured by TILDA. There were no changes in plasma viremia or inducible MS RNA in P1 or P2. With respect to gag-specific ICS, P2 demonstrated a striking increase in the frequency of central and effector memory CD8+ T cells producing IFN-γ, TNF-α, and CD107a (Fig1C-E), which were not demonstrated in P1 and P3.
Increases in HIV transcription were observed on ART in all three participants following each cycle of either anti-PD-L1 or anti-PD-1 + anti-CTLA-4, with variable effects on plasma viremia, TILDA and ICS. Our results highlight that ICB can perturb HIV latency and increase HIV-specific immune responses but with significant variation between individuals.