Recombinant human IL-15 (rhlL-15) in combination with anti-PD-L1(Avelumab) in SIV infected rhesus macaques leads to the expansion of a subset of CXCR3(+)PD1(-/low) CD8 T cells

Abstract The PD1/PD-L1 pathway contributes to the pathogenesis of HIV/SIV infection. Expression of PD1 by HIV/SIV-specific CD8 T cells can limit antiviral responses and expression of checkpoint receptors including PD1 by HIV infected cells can contribute to maintenance of viral reservoirs. In addition, reports have shown that IL-15 induces the expansion of effector memory CD8 T and NK cells. In this study, we hypothesized that expansion of memory CD8 T cells in the context of PD1/PD-L1 blockade may lead to enhanced anti-SIV responses. We design a study in which we evaluated the effect of rhIL-15 administered in cycles of ten days by continuous infusion in combination with weekly administration of anti-PD-L1 (Avelumab) over 24 weeks. After seven doses of anti-PD-L1 and completion of two cycles of rhIL15, cART therapy was interrupted and anti-PD-L1 administration continued to complete 24 weeks treatment. We found that administration of rhIL-15 in combination with anti-PD-L1 treatment was well tolerated. rhIL-15 infusions were associated with transient increases in proliferation of NK cells and effector memory CD8 T cells. rhIL-15/anti-PD-L1 treatment led to a sustained expression of CXCR3+ with low to undetectable expression of PD1on CD8 T cells, suggesting potential of increased tissue trafficking. Multidimensional single cell analysis showed that CXCR3+PD1−/low CD8 T cells secrete cytokine in response to viral antigens. Despite these clear biological effects, no impact was observed on rebound plasma viremia after cART discontinuation and during anti-PD-L1 administration. Futures studies should characterize the CXCR3+PD1−/low CD8 T cell subset expanded by this treatment to understand the potential impact of this subset in viral control.