Impact of KIR/HLA-C Interactions on the anti-HIV-1 Activity of NK Cells

Abstract

NK cells play a crucial role in antiviral immunity by utilizing a large array of activating and inhibitory receptors to identify and eliminate virus-infected cells. Killer-cell immunoglobulin-like receptors (KIR) represent a highly polymorphic receptor family, regulating NK cell activity. Human leukocyte antigen (HLA) class I molecules are expressed on almost all somatic cells and serve as a primary ligand for KIRs. HLA-C is the most recently evolved HLA class I molecule and serves as a ligand for the inhibitory KIR2DL receptors. Accumulating evidence indicate that HLA-C/KIR2DL interactions can drive HIV-1-mediated immune evasion and contributes to the intrinsic control of HIV-1 infection. However, little is known about the complex interplay of HLA-C/KIR2DL immunogenetics, NK cell-mediated immune pressure and HIV-1 immune escape. Based on the diverse and highly polymorphic combinations of HLA-C and KIR2DL and a potential importance in HIV-1 infection, this thesis aims to assess the impact of HLA-C and KIR2DL host genetics on NK cell activity in HIV-1 infection and immune evasion. Binding assays of HLA-C and KIR2DL combinations showed large differences in binding affinities between different combinations. CD107a degranulation assays revealed higher frequencies of CD107a in NK cells with inhibitory receptors for self-HLA class I molecules. Moreover, phenotypic characterization of NK cells revealed differences in NK cell receptor profiles between HIV-1+ and HIV-1- individuals and a genotype-dependent expansion of KIR2DL1+ NK cells in HIV-1+ individuals carrying the respective HLA-C2 ligand. Lastly, Vpu sequencing indicated a selection of Vpu sequence variants in association with high HLA-C allele expression and strong KIR2DL/HLA-C binding affinities. Altogether, the results of this thesis provide evidence that HIV-1 is associated with changes in the KIR repertoire of NK cells that to a certain extent are pre-determined by host HLA-C/KIR2DL genotypes. HLA-C expression level and HLA-C/KIR2DL binding affinities might have an impact on HIV-1 Vpu sequence polymorphisms as a potential mechanism to evade the host immune response.