HIV-1 induced changes in HLA-C*03 : 04-presented peptide repertoires lead to reduced engagement of inhibitory natural killer cell receptors
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HIV-1 induced changes in HLA-C*03 : 04-presented peptide repertoires lead to reduced engagement of inhibitory natural killer cell receptors. / 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.
In: AIDS, Vol. 34, No. 12, 01.10.2020, p. 1713-1723.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - HIV-1 induced changes in HLA-C*03 : 04-presented peptide repertoires lead to reduced engagement of inhibitory natural killer cell receptors
AU - Ziegler, Maja C
AU - Nelde, Annika
AU - Weber, Jeffrey K
AU - Schreitmüller, Christian M
AU - Martrus, Glòria
AU - Huynh, Tien
AU - Bunders, Madeleine J
AU - Lunemann, Sebastian
AU - Stevanovic, Stefan
AU - Zhou, Ruhong
AU - Altfeld, Marcus
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
KW - HIV Infections
KW - HIV-1
KW - HLA-C Antigens
KW - Humans
KW - Peptides
KW - Receptors, KIR
KW - Receptors, Natural Killer Cell
U2 - 10.1097/QAD.0000000000002596
DO - 10.1097/QAD.0000000000002596
M3 - SCORING: Journal article
C2 - 32501836
VL - 34
SP - 1713
EP - 1723
JO - AIDS
JF - AIDS
SN - 0269-9370
IS - 12
ER -