Dimorphic HLA-B signal peptides differentially influence HLA-E- and natural killer cell-mediated cytolysis of HIV-1-infected target cells

Authors

  • A. M. Merino,

    1. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
    2. Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
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  • S. Sabbaj,

    1. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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  • J. Easlick,

    1. Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
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  • P. Goepfert,

    1. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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  • R. A. Kaslow,

    1. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
    2. Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
    3. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
    Current affiliation:
    1. Department of Veterans Affairs, Washington, DC, USA
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  • J. Tang

    Corresponding author
    1. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
    2. Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
    • Correspondence: J. Tang, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

      E-mail: jtang@uab.edu

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Summary

As a mechanism of self-protection, signal peptides cleaved from human leukocyte antigen (HLA) class I products bind to HLA-E before the complex interacts with the natural killer (NK) cell receptor CD94/NKG2A to inhibit NK-mediated cell lysis. Two types of the signal peptides differ in their position 2 (P2) anchor residue, with P2-methionine (P2-M) having higher HLA-E binding affinity than P2-threonine (P2-T). All HLA-A and HLA-C molecules carry P2-M, whereas HLA-B products have either P2-M or P2-T. Epidemiological evidence suggests that P2-M is unfavourable in the context of HIV-1 infection, being associated with accelerated acquisition of HIV-1 infection in two African cohorts. To begin elucidating the functional mechanism, we studied NK-mediated killing of CD4+ T cells and monocyte-derived macrophages infected with two laboratory-adapted HIV-1 strains and two transmitted/founder (T/F) viruses. In the presence of target cells derived from individuals with the three HLA-B P2 genotypes (M/M, M/T and T/T), NK-mediated cytolysis was elevated consistently for P2-T in a dose-dependent manner for all cell and virus combinations tested (P = 0·008–0·03). Treatment of target cells with an anti-HLA-E monoclonal antibody restored NK-mediated cytolysis of cells expressing P2-M. Observations on cell lysis were also substantiated by measurements of HIV-1 p24 antigen in the culture supernatants. Overall, our experiments indicate that the anti-HIV-1 function mediated by NK cells is compromised by P2-M, corroborating the association of HLA-B genotype encoding P2-M with accelerated HIV-1 acquisition.

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