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HLA-B*14:02-RESTRICTED ENV-SPECIFIC CD8+ T-CELL ACTIVITY HAS HIGHLY POTENT ANTIVIRAL EFFICACY ASSOCIATED WITH IMMUNE CONTROL OF HIV INFECTION.

  1. Author:
    Leitman, Ellen M
    Willberg, Christian B
    Tsai, Ming-Han
    Chen, Huabiao
    Buus, Søren
    Chen, Fabian
    Riddell, Lynn
    Haas, David
    Fellay, Jacques
    Goedert, James J
    Piechocka-Trocha, Alicja
    Walker, Bruce D
    Martin, Jeffrey
    Deeks, Steven
    Wolinsky, Steven M
    Martinson, Jeremy
    Martin, Pat
    Qi, Ying
    Sáez-Cirión, Asier
    Yang, Otto O
    Matthews, Philippa C
    Carrington, Mary
    Goulder, Philip J R

  2. Author Address

    Department of Paediatrics, University of Oxford, Oxford, UK ellen_leitman@hms.harvard.edu., Harvard Medical School, Boston, Massachusetts, USA., Nuffield Department of Medicine, University of Oxford, Oxford, UK., Department of Paediatrics, University of Oxford, Oxford, UK., Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA., Vaccine and Immunotherapy Centre, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, Denmark., Department of Sexual Health, Royal Berkshire Hospital, Reading, UK., Integrated Sexual Health Services, Northamptonshire Healthcare NHS Trust, Northampton, UK., Departments of Medicine, Pharmacology, Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA., School of Life Sciences, Ecole Polytechnique F 233;d 233;rale de Lausanne; Swiss Institute of Bioinformatics, Lausanne, Switzerland., Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa., Department of Medicine, University of California San Francisco Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA., Department of Medicine, University of California, San Francisco, California, USA., Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA., Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Cancer and Inflammation Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Maryland, USA., Institut Pasteur, Unit 233; HIV, Inflammation et Persistance, Paris, France., Department of Medicine, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA., AIDS Healthcare Foundation, Los Angeles, California, USA., Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.,
    1. Year: 2017
    2. Date: NOV
    3. Epub Date: 2017 Sep 06
  2. Journal: Journal of virology
    1. 91
    2. 22
    3. Pages: pii: JVI.00544-17
  4. Type of Article: Article
  5. Article Number: UNSP e00544-17
  6. ISSN: 0022-538X
  1. Abstract:

    Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8+ T-cell responses. We here focus on HLA-B*14, that protects against HIV disease progression, but the immunodominant HLA-B*14-restricted anti-HIV response is Env-specific (ERYLKDQQL, 'HLA-B*14-EL9'). A subdominant HLA-B*14-restricted response targets Gag (DRYFKTLRA, 'HLA-B*14-DA9'). Using HLA-B*14/peptide-saporin conjugated tetramers, we show that HLA-B*14-EL9 is substantially more potent at inhibiting viral replication than HLA-B*14-DA9. HLA-B*14-EL9 also has significantly higher functional avidity (p< 0.0001) and drives stronger selection pressure on the virus than HLA-B*14-DA9. However, these differences were HLA-B*14 subtype-specific, applying only to HLA-B*14:02 and not HLA-B*14:01. Furthermore, the HLA-B*14-associated protection against HIV disease progression is significantly greater for HLA-B*14:02 than for HLA-B*14:01, consistent with the superior antiviral efficacy of the HLA-B*14-EL9 response. Thus, although Gag-specific CD8+ T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity of individual responses, are also critically important to immune control of HIV.IMPORTANCE In HIV infection, although CTL play a potentially critical role in eradication of viral reservoirs, the features that constitute an effective response remain poorly defined. We focus on HLA-B*14, unique among HLA associated with control of HIV in that the dominant CTL response is Env-specific, not Gag. We demonstrate that Env-specific HLA-B*14-restricted activity is substantially more efficacious than the subdominant HLA-B*14-restricted Gag response. Env immunodominance over Gag, and strong Env-mediated selection pressure on HIV, are only observed in subjects expressing HLA-B*14:02, and not HLA-B*14:01. This reflects increased functional avidity of Env response over Gag, substantially more marked for HLA-B*14:02. Finally, we show that HLA-B*14:02 is significantly more strongly associated with viraemic control than HLA-B*14:01. These findings indicate that, although Gag-specific CTL may usually have greater anti-HIV efficacy than Env responses, factors independent of protein specificity, including functional avidity, may carry greater weight in mediating effective control of HIV. Copyright © 2017 Leitman et al.

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External Sources

  1. View Full Text
  2. DOI: 10.1128/JVI.00544-17
  3. PMID: 28878089
  4. View record in Web of Science®
  5. WOS: 000414005400001

Library Notes

  1. Fiscal Year: FY2016-2017
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