PD-L1 Blockade Differentially Impacts Regulatory T Cells from HIV-Infected Individuals Depending on Plasma Viremia

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.

Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals

“…Differences in response to inhibitory receptor blockade treatment have also been shown in murine studies and in human T cells from HIV-infected subjects, where not all individuals responded equally to treatment2425. Therefore, the potential usefulness of HIV-specific CD8 + T cells to eliminate target cells in immune based curative strategies requires further investigation with a particular emphasis of the T cell exhaustion process, including the role of TIGIT.…”

CD8 T‐cell regulation by T regulatory cells and the programmed cell death protein 1 pathway

“…Interestingly, PD‐L1 blockade during chronic LCMV or HIV infection results in exaggerated expansion of Treg cells and up‐regulation of inhibitory markers . These data demonstrate that the PD‐1 pathway not only inhibits exhausted CD8 T cells, but also inhibits Treg cells.…”

Cell and gene therapy strategies to eradicate HIV reservoirs

“…While initial studies of latency reversing agents showed limited induction of viral RNA expression in vivo [81], new reagents like GS-9620, a TLR-7 agonist developed by Gilead, seem very promising and may prove useful with CAR T cell therapies [82]. Furthermore, since HIV-specific CD4+ and CD8+T cells can lose their effector functions and proliferative capacity in a phenomenon known as immune exhaustion [83] mediated by programed death 1 (PD-1), blockade of the PD-1 pathway may restore impaired anti-HIV immune responses [84], [85]. This may be of particular importance for cell-based therapies such as anti-HIV CAR T cells.…”