{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:06:52Z","timestamp":1791875212388,"version":"4.3.4"},"reference-count":81,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T00:00:00Z","timestamp":1657843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>NK cells play a pivotal role in viral immunity, utilizing a large array of activating and inhibitory receptors to identify and eliminate virus-infected cells. Killer-cell immunoglobulin-like receptors (KIRs) represent a highly polymorphic receptor family, regulating NK cell activity and determining the ability to recognize target cells. Human leukocyte antigen (HLA) class I molecules serve as the primary ligand for KIRs. Herein, HLA-C stands out as being the dominant ligand for the majority of KIRs. Accumulating evidence indicated that interactions between HLA-C and its inhibitory KIR2DL receptors (KIR2DL1\/L2\/L3) can drive HIV-1-mediated immune evasion and thus may contribute to the intrinsic control of HIV-1 infection. Of particular interest in this context is the recent observation that HIV-1 is able to adapt to host<jats:italic>HLA-C<\/jats:italic>genotypes through Vpu-mediated downmodulation of HLA-C. However, our understanding of the complex interplay between<jats:italic>KIR\/HLA<\/jats:italic>immunogenetics, NK cell-mediated immune pressure and HIV-1 immune escape is still limited. Therefore, we investigated the impact of specific<jats:italic>KIR\/HLA-C<\/jats:italic>combinations on the NK cell receptor repertoire and HIV-1 Vpu protein sequence variations of 122 viremic, untreated HIV-1<jats:sup>+<\/jats:sup>individuals. Compared to 60 HIV-1<jats:sup>-<\/jats:sup>controls, HIV-1 infection was associated with significant changes within the NK cell receptor repertoire, including reduced percentages of NK cells expressing NKG2A, CD8, and KIR2DS4. In contrast, the NKG2C<jats:sup>+<\/jats:sup>and KIR3DL2<jats:sup>+<\/jats:sup>NK cell sub-populations from HIV-1<jats:sup>+<\/jats:sup>individuals was enlarged compared to HIV-1<jats:sup>-<\/jats:sup>controls. Stratification along<jats:italic>KIR\/HLA-C<\/jats:italic>genotypes revealed a genotype-dependent expansion of KIR2DL1<jats:sup>+<\/jats:sup>NK cells that was ultimately associated with increased binding affinities between KIR2DL1 and HLA-C allotypes. Lastly, our data hinted to a preferential selection of Vpu sequence variants that were associated with HLA-C downmodulation in individuals with high KIR2DL\/HLA-C binding affinities. Altogether, our study provides evidence that HIV-1-associated changes in the KIR repertoire of NK cells are to some extent predetermined by host<jats:italic>KIR2DL\/HLA-C<\/jats:italic>genotypes. Furthermore, analysis of Vpu sequence polymorphisms indicates that differential KIR2DL\/HLA-C binding affinities may serve as an additional mechanism how host genetics impact immune evasion by HIV-1.<\/jats:p>","DOI":"10.3389\/fimmu.2022.922252","type":"journal-article","created":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T06:40:40Z","timestamp":1657867240000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Host KIR\/HLA-C Genotypes Determine HIV-Mediated Changes of the NK Cell Repertoire and Are Associated With Vpu Sequence Variations Impacting Downmodulation of 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