Impact of KIR/HLA-C interactions on the anti-HIV activity of NK cells

• Applicant: Dr. Christian Körner
• Subject Area: Immunology ; Virology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 410760607

Infection with the human immune deficiency virus (HIV) remains an eventually fatal disease in the absence of antiretroviral therapy. The difficulties to control the infection partially arise from numerous strategies HIV developed to evade host immune responses. Recently primary HIV isolates were identified that are able to downmodulate HLA-C through the accessory HIV protein Vpu leading to loss of recognition by T cells. Vpu-mediated modulation of HLA-C therefore represents a novel immune evasion mechanism and challenges previously established models. In this context, the applicant recently showed that NK cells expressing inhibitory KIR2DL receptors were able to sense HIV-mediated alterations of HLA-C surface expression on infected cells. These highly polymorphic receptors recognize HLA-C with differential affinities and dominate NK-cell responses. Given the extended polymorphism of HLA-C and KIR2DL receptors it is yet unknown to what extent KIR2DL/HLA-C allotype combinations determine the ability of NK cells to efficiently recognize HIV-infected cells, in particular in the setting of HIV-mediated downmodulation of HLA-C. Based on these findings, we hypothesize that KIR2DL/HLA-C interactions represent a major determinant for the magnitude of NK-cell-mediated immune pressure and potentially impact HIV disease progression. This proposal aims to investigate the impact of KIR2DL/HLA-C interactions on the anti-HIV activity of NK cells in the setting of HIV-mediated HLA-C downmodulation. Furthermore, we seek to determine the effects of KIR2DL/HLA-C interactions on Vpu-associated viral evolution in vivo and in vitro. Using an autologous in vitro infection system the anti-HIV activity of KIR2DL+ NK cells will be assessed. Additionally, NK-cell-driven viral evolution within Vpu will be identified in primary isolates and in vitro through next generation sequencing. Altogether, the results obtained from this proposal will provide critical information on the mechanisms underlying NK-cell-mediated recognition of HIV-infected cells and the ability of HIV to evade NK-cell-mediated immune pressure by modulating HLA-C expression.

• DFG Programme: Research Grants