HIV-1 induced changes in HLA-C*03 :  04-presented peptide repertoires lead to reduced engagement of inhibitory natural killer cell receptors. (1st October 2020)

• Record Type: Journal Article
• Authors: Ziegler, Maja C.; Nelde, Annika; Weber, Jeffrey K.; Schreitmüller, Christian M.; Martrus, Glòria; Huynh, Tien; Bunders, Madeleine J.; Lunemann, Sebastian; Stevanovic, Stefan; Zhou, Ruhong; Altfeld, Marcus
• Is Part Of: AIDS. Volume 34:Number 12(2020)
• Publication Date: 2020-10-01
• Subjects: HIV-1 infection -- HLA-C*03 : 04 -- HLA-I -- HLA-I presented peptide repertoire -- killer immunoglobuline-like receptor -- KIR2DL3 -- natural killer cells; AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome; AIDS (Disease); Periodicals; Periodicals; 616.9792005
• DOI: 10.1097/QAD.0000000000002596
• Languages: English
• ISSNs: 0269-9370

Abstract

Abstract : Objective: Viral infections influence intracellular peptide repertoires available for presentation by HLA-I. Alterations in HLA-I/peptide complexes can modulate binding of killer immunoglobuline-like receptors (KIRs) and thereby the function of natural killer (NK) cells. Although multiple studies have provided evidence that HLA-I/KIR interactions play a role in HIV-1 disease progression, the consequence of HIV-1 infection for HLA-I/KIR interactions remain largely unknown. Design: We determined changes in HLA-I presented peptides resulting from HIV-1-infection of primary human CD4 + T cells and assessed the impact of changes in peptide repertoires on HLA-I/KIR interactions. Methods: Liquid chromatography-coupled tandem mass spectrometry to identify HLA-I presented peptides, cell-based in-vitro assays to evaluate functional consequences of alterations in immunopeptidome and atomistic molecular dynamics simulations to confirm experimental data. Results: A total of 583 peptides exclusively presented on HIV-1-infected cells were identified, of which only 0.2% represented HIV-1 derived peptides. Focusing on HLA-C*03 : 04/KIR2DL3 interactions, we observed that HLA-C*03 : 04-presented peptides derived from noninfected CD4 + T cells mediated stronger binding of inhibitory KIR2DL3 than peptides derived from HIV-1-infected cells. Furthermore, the most abundant peptide presented by HLA-C*03 : 04 on noninfected CD4 + T cells (VIYPARISL) mediated the strongest KIR2DL3-binding, while the most abundant peptide presented on HIV-1-infected cells (YAIQATETL) did not mediate KIR2DL3-binding. Molecular dynamics simulations of HLA-C*03 : 04/KIR2DL3 interactions in the context of these two peptides revealed that VIYPARISL significantly enhanced the HLA-C*03 : 04/peptide contact area to KIR2DL3 compared with YAIQATETL. Conclusion: These data demonstrate that HIV-1 infection-induced changes in HLA-I-presented peptides can reduce engagement of inhibitory KIRs, providing a mechanism for enhanced activation of NK cells by virus-infected cells. Abstract : Supplemental Digital Content is available in the text