In vivo effect of anti-PD-1 on HIV-specific CD8+T-cells in men with HIV.

One approach to achieve a cure for HIV infection or allow for people with HIV to safely stop antiretroviral therapy is to enhance HIV-specific immune function by reversing immune exhaustion. Immune checkpoint blockade with anti-PD1 can enhance virus-specific T-cell function ex vivo and in animal models but the effects of anti-PD1 on HIV-specific T-cells in vivo has not been explored. We examine samples from men with HIV and cancer on antiretroviral therapy who receive nivolumab (anti-PD1) every two weeks as part of a prospective clinical trial. We show that a single dose of anti-PD-1 increases HIV-specific CD8 + T cells in some but not all participants. Using single cell RNAseq of HIV-specific CD8 + T-cells, we show that anti-PD-1 significantly reshapes the T-cell landscape. Following anti-PD1, we see the emergence of a distinct 'progenitor' like central memory cluster characterized by an interferon-stimulated gene signature as well as an increase in expression of Granzyme-H in memory cells with expanded T-cell receptors, highlighting potential pathways to reinvigoration of cytotoxic function. We also demonstrate an inverse relationship between an increase in cell associated viral RNA following anti-PD-1 and the percentage of specific T-cell clusters prior to administration of anti-PD-1. These findings demonstrate the multiple effects of anti-PD-1 on both HIV-specific CD8 + T cells and HIV latency in PWH on ART.