ART has dramatically improved life expectancy for PLWH but it needs to be taken lifelong and immune dysfunction persists with elevated expression of immune checkpoints (IC) including programmed death (PD-1) and cytotoxic T lymphocyte Antigen (CTLA-4). In individuals with cancer, IC blockade (ICB) augments tumour-directed T cell responses resulting in significant clinical cures. Recently, a subset of transcription factor T cell factor 1 (TCF1) expressing precursor exhausted T cells (Tpex) were shown to be responsible for the proliferative burst and increased effector functions of CD8 T cells after ICB. There is high interest in whether ICB can drive recovery of HIV-specific T-cell cytolytic function in PLWH on suppressive ART.
In a phase one clinical trial, where PLWH on ART with cancer received ICB (anti-PD1 alone or anti-CTLA-4 in combination with anti-PD1), we quantified HIV-specific T-cell function prior to and on at least 2 time points during treatment. We stimulated peripheral blood mononuclear cells (PBMC) from six participants with pools of overlapping Gag and Nef peptides and measured the percentage of TNFa and IFNg producing CD8 T cells to identify polyfunctional T-cells.
We identified two participants who had a >2 fold increase in the frequency of HIV-specific cytokine-producing CD8 T cells following ICB. Next we determined the frequency of Tpex cells (defined as CD8+PD1+TCF1+GzyB-CD45RA-) at baseline in these six participants and found that Tpex frequency was highest in the two participants with increased CD8 HIV response (3.1% and 1.7% compared to mean <0.9%).
We identified two participants with an increase in polyfunctional HIV specific CD8 T cells following ICB. These same participants had a high frequency of Tpex cells at baseline which potentially predicts an effective response to ICB. ICB can enhance HIV-specific T-cell function and should be further explored as a component of cure strategies.