HLA-B*14:02-Restricted Env-Specific CD8 + T-Cell Activity Has Highly Potent Antiviral Efficacy Associated with Immune Control of HIV Infection.

Autor:	Leitman EM; Department of Paediatrics, University of Oxford, Oxford, United Kingdom ellen_leitman@hms.harvard.edu.; Harvard Medical School, Boston, Massachusetts, USA., Willberg CB; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Tsai MH; Department of Paediatrics, University of Oxford, Oxford, United Kingdom., Chen H; Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.; Vaccine and Immunotherapy Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., Buus S; Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark., Chen F; Department of Sexual Health, Royal Berkshire Hospital, Reading, United Kingdom., Riddell L; Integrated Sexual Health Services, Northamptonshire Healthcare NHS Trust, Northampton, United Kingdom., Haas D; Departments of Medicine, Pharmacology, Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA., Fellay J; School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Swiss Institute of Bioinformatics, Lausanne, Switzerland., Goedert JJ; Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Piechocka-Trocha A; Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA., Walker BD; Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.; HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa., Martin J; Department of Medicine, University of California San Francisco Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA., Deeks S; Department of Medicine, University of California, San Francisco, California, USA., Wolinsky SM; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.; Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA., Martinson J; Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Martin M; Cancer and Inflammation Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA., Qi Y; Cancer and Inflammation Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA., Sáez-Cirión A; Institut Pasteur, Unité HIV, Inflammation et Persistance, Paris, France., Yang OO; Department of Medicine, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.; AIDS Healthcare Foundation, Los Angeles, California, USA., Matthews PC; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.; Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom., Carrington M; Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.; Cancer and Inflammation Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA., Goulder PJR; Department of Paediatrics, University of Oxford, Oxford, United Kingdom.; HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
Jazyk:	angličtina
Zdroj:	Journal of virology [J Virol] 2017 Oct 27; Vol. 91 (22). Date of Electronic Publication: 2017 Oct 27 (Print Publication: 2017).
DOI:	10.1128/JVI.00544-17
Abstrakt:	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, which 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 to 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 cytotoxic T lymphocytes (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 HLAs associated with control of HIV in that the dominant CTL response is Env specific, not Gag specific. 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 observed only in subjects expressing HLA-B*14:02, and not HLA-B*14:01. This reflects the increased functional avidity of the 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 viremic 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.)
Databáze:	MEDLINE
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