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. 2020 Oct 1;34(12):1713-1723.
doi: 10.1097/QAD.0000000000002596.

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

Maja C Ziegler  1 , Annika Nelde  2 , Jeffrey K Weber  3 , Christian M Schreitmüller  2 , Glòria Martrus  1 , Tien Huynh  3 , Madeleine J Bunders  1 , Sebastian Lunemann  1 , Stefan Stevanovic  2 , Ruhong Zhou  3 , Marcus Altfeld  1
Affiliations

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

Maja C Ziegler et al. AIDS. .

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.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

Figures

Fig. 1
Fig. 1
Analysis of the immunopeptidome of primary HIV-1-infected CD4+ T cells by mass spectrometry.
Fig. 2
Fig. 2
HLA-I-presented peptides derived from HIV-1.
Fig. 3
Fig. 3
Overlap analysis illustrating the numbers of HLA-I/HLA-C∗03 : 04-restricted peptides identified under the different conditions.
Fig. 4
Fig. 4
Interaction of peptides, HLA-C∗03 : 04 and KIR2DL3 in vitro.
Fig. 5
Fig. 5
Molecular dynamics simulations of HLA-I/peptide-KIR complexes.
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