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

Abstract

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. In people living with HIV, long term viral infection, even in the face of successful therapeutic control of viral load, can result in increased numbers of exhausted CD8+ T cells. Here the authors assess the in vivo effect of anti-PD-1 antibody therapy on the HIV specific CD8+ T cell response in men with HIV.