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Host 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. | LitMetric

AI Article Synopsis

  • NK cells are crucial for fighting viral infections and use a variety of receptors, with HLA-C being the main ligand for Killer-cell immunoglobulin-like receptors (KIRs), influencing NK cell activity.
  • The study shows that HIV-1 can evade the immune response by adapting to host genetics, particularly through the Vpu protein that downregulates HLA-C, which helps the virus escape detection by NK cells.
  • Researchers found that HIV-1 infection leads to changes in the NK cell receptor profile, including an increase in specific NK cell populations and a genotype-dependent expansion of KIR2DL1, indicating a complex relationship between the immune response and HIV-1 evolution.

Article Abstract

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 genotypes through Vpu-mediated downmodulation of HLA-C. However, our understanding of the complex interplay between immunogenetics, NK cell-mediated immune pressure and HIV-1 immune escape is still limited. Therefore, we investigated the impact of specific 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 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 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9334850PMC
http://dx.doi.org/10.3389/fimmu.2022.922252DOI Listing

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