biostudies-literatureVollmers SNIAID NIH HHS922252https://www.ebi.ac.uk/biostudies/studies/S-EPMC9334850biostudies-literatureUnknown13NK 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 <i>HLA-C</i> genotypes through Vpu-mediated downmodulation of HLA-C. However, our understanding of the complex interplay between <i>KIR/HLA</i> immunogenetics, NK cell-mediated immune pressure and HIV-1 immune escape is still limited. Therefore, we investigated the impact of specific <i>KIR/HLA-C</i> combinations on the NK cell receptor repertoire and HIV-1 Vpu protein sequence variations of 122 viremic, untreated HIV-1⁺ individuals. Compared to 60 HIV-1^- 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⁺ and KIR3DL2⁺ NK cell sub-populations from HIV-1⁺ individuals was enlarged compared to HIV-1^- controls. Stratification along <i>KIR/HLA-C</i> genotypes revealed a genotype-dependent expansion of KIR2DL1⁺ 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 <i>KIR2DL/HLA-C</i> 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.Frontiers in immunologyHost KIR/HLA-C Genotypes Determine HIV-Mediated Changes of the NK Cell Repertoire and Are Associated With Vpu Sequence Variations Impacting Downmodulation of HLA-C.PMC9334850R01 AI158410Wyen CKorner CBrias SSchmidt AHHoelzemer AFittje PVirdi SMeurer ASauer GIndenbirken DWolf ESauter JBehrens GMNPostel NVollmers SPeine SRichert LLehmann CRoider JStephan CLobermeyer ATrenkner TPauli RScholten SSpinner CDAltfeld MNiehrs ANakel JNorman PJfalseHost KIR/HLA-C Genotypes Determine HIV-Mediated Changes of the NK Cell Repertoire and Are Associated With Vpu Sequence Variations Impacting Downmodulation of HLA-C.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 <i>HLA-C</i> genotypes through Vpu-mediated downmodulation of HLA-C. However, our understanding of the complex interplay between <i>KIR/HLA</i> immunogenetics, NK cell-mediated immune pressure and HIV-1 immune escape is still limited. Therefore, we investigated the impact of specific <i>KIR/HLA-C</i> combinations on the NK cell receptor repertoire and HIV-1 Vpu protein sequence variations of 122 viremic, untreated HIV-1⁺ individuals. Compared to 60 HIV-1^- 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⁺ and KIR3DL2⁺ NK cell sub-populations from HIV-1⁺ individuals was enlarged compared to HIV-1^- controls. Stratification along <i>KIR/HLA-C</i> genotypes revealed a genotype-dependent expansion of KIR2DL1⁺ 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 <i>KIR2DL/HLA-C</i> 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-1.2022-01-01T00:00:00Z20222024-11-10T03:37:50.894Z2024-11-10T03:37:50.894ZS-EPMC93348503591176210.3389/fimmu.2022.922252