Vollmers, Sarah, Lobermeyer, Annabelle, Niehrs, Annika, Fittje, Pia ORCID: 0000-0002-0123-9844, Indenbirken, Daniela, Nakel, Jacqueline, Virdi, Sanamjeet, Brias, Sebastien, Trenkner, Timo, Sauer, Gabriel, Peine, Sven, Behrens, Georg M. N., Lehmann, Clara, Meurer, Anja, Pauli, Ramona, Postel, Nils, Roider, Julia, Scholten, Stefan, Spinner, Christoph D., Stephan, Christoph ORCID: 0000-0003-3777-9006, Wolf, Eva, Wyen, Christoph, Richert, Laura, Norman, Paul J., Sauter, Juergen, Schmidt, Alexander H., Hoelzemer, Angelique, Altfeld, Marcus ORCID: 0000-0001-5972-2997 and Koerner, Christian (2022). 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. Front. Immunol., 13. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1664-3224

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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 HLA-C genotypes through Vpu-mediated downmodulation of HLA-C. However, our understanding of the complex interplay between KIR/HLA immunogenetics, NK cell-mediated immune pressure and HIV-1 immune escape is still limited. Therefore, we investigated the impact of specific KIR/HLA-C 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 KIR/HLA-C 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 KIR2DL/HLA-C 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Vollmers, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lobermeyer, AnnabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niehrs, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fittje, PiaUNSPECIFIEDorcid.org/0000-0002-0123-9844UNSPECIFIED
Indenbirken, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nakel, JacquelineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Virdi, SanamjeetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brias, SebastienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trenkner, TimoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sauer, GabrielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peine, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Behrens, Georg M. N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehmann, ClaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meurer, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pauli, RamonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Postel, NilsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roider, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scholten, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spinner, Christoph D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stephan, ChristophUNSPECIFIEDorcid.org/0000-0003-3777-9006UNSPECIFIED
Wolf, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wyen, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richert, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Norman, Paul J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sauter, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, Alexander H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelzemer, AngeliqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altfeld, MarcusUNSPECIFIEDorcid.org/0000-0001-5972-2997UNSPECIFIED
Koerner, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-695441
DOI: 10.3389/fimmu.2022.922252
Journal or Publication Title: Front. Immunol.
Volume: 13
Date: 2022
Publisher: FRONTIERS MEDIA SA
Place of Publication: LAUSANNE
ISSN: 1664-3224
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NATURAL-KILLER-CELLS; HUMAN CYTOMEGALOVIRUS-INFECTION; INHIBITORY RECEPTORS; SURFACE EXPRESSION; BINDING; KIR; EXPANSION; RECOGNITION; KIR2DL2; REVEALSMultiple languages
ImmunologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69544

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