Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa
Year: 2015
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Viruses can evade immune surveillance, but the underlying mechanisms are insufficiently understood. Here, we sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK-cell-mediated immune pressure. METHODS AND FINDINGS: Two sequence mutations in p24 Gag associated with the presence of specific KIR/HLA combined genotypes were identified in HIV-1 clade C viruses from a large cohort of infected, untreated individuals in South Africa (n = 392), suggesting viral escape from KIR+ NK cells through sequence variations within HLA class I-presented epitopes. One sequence polymorphism at position 303 of p24 Gag (TGag303V), selected for in infected individuals with both KIR2DL3 and HLA-C*03:04, enabled significantly better binding of the inhibitory KIR2DL3 receptor to HLA-C*03:04-expressing cells presenting this variant epitope compared to the wild-type epitope (wild-type mean 18.01 ± 10.45 standard deviation [SD] and variant mean 44.67 ± 14.42 SD, p = 0.002). Furthermore, activation of primary KIR2DL3+ NK cells from healthy donors in response to HLA-C*03:04+ target cells presenting the variant epitope was significantly reduced in comparison to cells presenting the wild-type sequence (wild-type mean 0.78 ± 0.07 standard error of the mean [SEM] and variant mean 0.63 ± 0.07 SEM, p = 0.012). Structural modeling and surface plasmon resonance of KIR/peptide/HLA interactions in the context of the different viral sequence variants studied supported these results. Future studies will be needed to assess processing and antigen presentation of the investigated HIV-1 epitope in natural infection, and the consequences for viral control. CONCLUSIONS: These data provide novel insights into how viruses can evade NK cell immunity through the selection of mutations in HLA-presented epitopes that enhance binding to inhibitory NK cell receptors. Better understanding of the mechanisms by which HIV-1 evades NK-cell-mediated immune pressure and the functional validation of a structural modeling approach will facilitate the development of novel targeted immune interventions to harness the antiviral activities of NK cells.
Source: PLoS Medicine
Authors: Angelique Hölzemer, Christina F. Thobakgale, Camilo A. Jimenez Cruz, Wilfredo F. Garcia-Beltran, Jonathan M. Carlson, Nienke H. van Teijlingen, Jaclyn K. Mann, Manjeetha Jaggernath, Seung-gu Kang, Christian Körner, Amy W. Chung, Jamie L. Schafer, David T. Evans, Galit Alter, Bruce D. Walker, Philip J. Goulder, Mary Carrington, Pia Hartmann, Thomas Pertel, Ruhong Zhou, Thumbi Ndung’u, Marcus Altfeld
Institutions: Leibniz Institute of Virology (LIV), Ragon Institute of MGH, MIT and Harvard, University Medical Center Hamburg-Eppendorf, Massachusetts Institute of Technology, University of KwaZulu-Natal, IBM Research - Thomas J. Watson Research Center, Microsoft (United States), Amsterdam UMC Location University of Amsterdam, Harvard University, University of Wisconsin–Madison, University of Oxford, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc. (United States), University of Cologne, Brigham and Women's Hospital, Max Planck Institute for Infection Biology
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,460
Funders: Howard Hughes Medical Institute, U.S. Department of Health and Human Services, Harvard University, Harvard University Center for AIDS Research, Deutsches Zentrum für Infektionsforschung, Wellcome Trust, Frederick National Laboratory for Cancer Research, Ragon Institute of MGH, MIT and Harvard, National Research Foundation, Deutscher Akademischer Austauschdienst, Bundesministerium für Bildung und Forschung, Victor Daitz Foundation, National Institutes of Health, Center for AIDS Research, University of Washington, Leibniz-Gemeinschaft, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Center for Complementary and Alternative Medicine, Cilag
Awards: G1203476693, G1521411027, G1575283533, G1722716446, G2225693873, Fcgamma receptor-mediated suppression of immunodeficiency virus replication, Klinische Forschergruppe in der klinischen Infektiologie: HIV-Infektion und Infektionen bei Immunsuppression, G3125303757, Lentiviral Resistance to Tetherin, G345173699, G3503792436, Medical Scientist Training Program, G3544613207, G3547560438, G379698727, G386607036, G4166928756, G4585269469, G468792422, G4756138391, Pathogenesis of Clade C HIV Infection, G4988656331, G5366891077, G5520316217, Natural Killer Cell Mediated Recognition of HIV-1 and Adaption to KIR and HLA., G5737582129, G5767575880, G5803924101, G5867949827, G5888954722, Identifying the ligand for the activating NK cell receptor KIR3DS1 and its protective role in HIV-1 disease progression, Natural Killer Cell Mediated Recognition of HIV-1 and Adaption to KIR and HLA., KIR and MHC Class I Immunogenetics in SIV Infection, G7300258001, G7785852513, Optimizing CD8+ T-cell responses against C clade HIV infection in subSaharan Afri, Mechanisms of HIV disease limitation and cure revealed in paediatric infection ., G8245670873, G8447644256, G9000108697, G9000129761, G9000180070, Harvard University Center for AIDS Research
OpenAlex ID: W2175125998