Assessing the in-vitro effects of anti-PD-L1 (Avelumab) and recombinant human rhIL-15 in CD8 T cell function from HIV infected patients

Abstract

Abstract Persistent immune activation in chronic HIV infection leads to exhaustion/activation of virus-specific CD8 T cells accompanied by expression of checkpoint receptors such as PD1. Here, we hypothesized that blockade of the PD1/PD-L1 pathway in combination with IL-15 (known to induce proliferation of CD8 T cells) may have a higher impact in improving HIV-specific responses. We assessed the in vitro effects of a checkpoint inhibitor, anti-PD-L1 (Avelumab), in combination with rhIL15 in HIV-specific CD8 T cell proliferation and cytokine secretion. Cell Trace Violet (CTV) labeled PBMCs from HIV infected patients (HIV+, n= 15) and healthy controls (HC, n= 7) were stimulated with HIVGag and CEF-peptides in the following conditions: rhIL-15, anti-PD-L1, and combination rhIL- 15/anti-PD-L1. After 5 days of culture, cells were re-stimulated and analyzed by flow cytometry. We found that rhIL-15 promoted higher antigen-independent proliferation (CTVlow) and cytokine secretion IFNg+ (p=0.009) and TNFa+ (p=0.01) in CD8 T cells from HIV+ patients than HC. In addition, rhIL-15 induced an increased trend in HIVGag-specific CD8 T cells (CTVlowIFNg+) but did not reach significance (p=0.1250). In HC, rhIL15 increased CEF-specific CD8 T cell CTVlowIFNg+ (p=0.03) and TNFa+ (p=0.03). Anti-PD-L1 alone did not show any effect in CD8 T cells from HIV+ patients and HC. In contrast, the combined treatment increased the CTVlowIFNg+ HIVGag-specific CD8 T cells in HIV+ patients (p=0.039) and CTVlowIFNg+ CEF-specific CD8 T cells in HC (p= 0.031). Overall, there was a synergistic effect in HIV-specific CD8 T cell function with the combined treatment. Further studies should assess the potential use of this combined treatment in the context of HIV infection.