Abstract
Blocking the PD-1/PD-L1 pathway has emerged as a potential therapy to restore impaired immune responses in human immunodeficiency virus (HIV)-infected individuals. Most reports have studied the impact of the PD-L1 blockade on effector cells and neglected possible effects on regulatory T cells (Treg cells), which play an essential role in balancing immunopathology and antiviral effector responses. The aim of this study was to define the consequences of ex vivo PD-L1 blockade on Treg cells from HIV-infected individuals. We observed that HIV infection led to an increase in PD-1+ and PD-L1+ Treg cells. This upregulation correlated with disease progression and decreased under antiretroviral treatment. Treg cells from viremic individuals had a particularly high PD-1 expression and impaired proliferative capacity in comparison with Treg cells from individuals under antiretroviral treatment. PD-L1 blockade restored the proliferative capacity of Treg cells from viremic individuals but had no effect on its suppressive capacity. Moreover, it increased the viral production in cell cultures from viremic individuals. This increase in viral production correlated with an increase in Treg cell percentage and a reduction in the CD4/Treg and CD8/Treg cell ratios. In contrast to the effect of the PD-L1 blockade on Treg cells from viremic individuals, we did not observe a significant effect on the proliferative capacity of Treg cells from individuals in whom viremia was controlled (either spontaneously or by antiretroviral treatment). However, PD-L1 blockade resulted in an increased proliferative capacity of HIV-specific-CD8 T cells in all subjects. Taken together, our findings suggest that manipulating PD-L1 in vivo can be expected to influence the net gain of effector function depending on the subject’s plasma viremia.
Highlights
Inhibiting programmed cell death 1 (PD-1) signalling has a potential therapeutic value for treating cancers and persistent viral infections
human immunodeficiency virus (HIV) infection causes a progressive impairment of effector immune responses, contributing to virus persistence
One strategy that could restore effector immune responses is the relief of the inhibitory signal displayed by the PD-1/programmed death ligand-1 (PD-L1) pathway on effector cells
Summary
Inhibiting programmed cell death 1 (PD-1) signalling has a potential therapeutic value for treating cancers and persistent viral infections (reviewed in [1,2,3,4,5]). Exhausted T cells present defects in effector function including impaired proliferation, cytotoxic capacity and cytokine production These defects can be partially restored by blocking the interaction between PD-1 and its ligand programmed death ligand-1 (PD-L1), which notably reduces viral loads in several animal infection models [7,8,9,10]. Since the HIV load is directly correlated with disease progression [17], an augmentation of antiviral immune responses by blocking the PD-1/PD-L1 pathway might help to control viral replication and slow down pathogenesis It may facilitate clearance of latently infected cells, and may represent a promising strategy to reach a functional cure of HIV infection [18,19]
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