Send to

Choose Destination
J Virol. 2018 Jan 30;92(4). pii: e01685-17. doi: 10.1128/JVI.01685-17. Print 2018 Feb 15.

Differential Immunodominance Hierarchy of CD8+ T-Cell Responses in HLA-B*27:05- and -B*27:02-Mediated Control of HIV-1 Infection.

Author information

Department of Paediatrics, University of Oxford, United Kingdom.
Department of GU Medicine, The Churchill Hospital, Oxford University NHS Foundation Trust, Oxford, United Kingdom.
Department of Sexual Health, Royal Berkshire Hospital, Reading, United Kingdom.
Department of Immunopathology of Infectious and Parasitic Diseases, Hospital for Infectious Diseases, Medical University of Warsaw, Warsaw, Poland.
Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Centre for Research in Infectious Diseases, National Institute of Respiratory Diseases, Mexico City, Mexico.
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Centre for Sexual Health and HIV Research, Mortimer Market Centre, London, United Kingdom.
Department of Medicine I, University Hospital Bonn, Bonn, Germany.
AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, Badalona, Spain.
University of Vic-Central University of Catalonia (UVic-UCC), Vic, Barcelona, Spain.
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
Department of Paediatrics, Imperial College, London, United Kingdom.
Oxford Martin School, University of Oxford, Oxford, United Kingdom.
Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Institute of Immunology and Infectious Diseases, Murdoch University, Perth, Australia.
San Francisco Department of Public Health, HIV Research Section, San Francisco, California, USA.
Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA.
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
School of Life Sciences, EPFL, Lausanne, Switzerland.
Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.
Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom.
Immunocore Limited, Abingdon, Oxfordshire, United Kingdom.
Cancer and Inflammation Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Maryland, USA.
Department of Paediatrics, University of Oxford, United Kingdom


The well-characterized association between HLA-B*27:05 and protection against HIV disease progression has been linked to immunodominant HLA-B*27:05-restricted CD8+ T-cell responses toward the conserved Gag KK10 (residues 263 to 272) and polymerase (Pol) KY9 (residues 901 to 909) epitopes. We studied the impact of the 3 amino acid differences between HLA-B*27:05 and the closely related HLA-B*27:02 on the HIV-specific CD8+ T-cell response hierarchy and on immune control of HIV. Genetic epidemiological data indicate that both HLA-B*27:02 and HLA-B*27:05 are associated with slower disease progression and lower viral loads. The effect of HLA-B*27:02 appeared to be consistently stronger than that of HLA-B*27:05. In contrast to HLA-B*27:05, the immunodominant HIV-specific HLA-B*27:02-restricted CD8+ T-cell response is to a Nef epitope (residues 142 to 150 [VW9]), with Pol KY9 subdominant and Gag KK10 further subdominant. This selection was driven by structural differences in the F pocket, mediated by a polymorphism between these two HLA alleles at position 81. Analysis of autologous virus sequences showed that in HLA-B*27:02-positive subjects, all three of these CD8+ T-cell responses impose selection pressure on the virus, whereas in HLA-B*27:05-positive subjects, there is no Nef VW9-mediated selection pressure. These studies demonstrate that HLA-B*27:02 mediates protection against HIV disease progression that is at least as strong as or stronger than that mediated by HLA-B*27:05. In combination with the protective Gag KK10 and Pol KY9 CD8+ T-cell responses that dominate HIV-specific CD8+ T-cell activity in HLA-B*27:05-positive subjects, a Nef VW9-specific response is additionally present and immunodominant in HLA-B*27:02-positive subjects, mediated through a polymorphism at residue 81 in the F pocket, that contributes to selection pressure against HIV.IMPORTANCE CD8+ T cells play a central role in successful control of HIV infection and have the potential also to mediate the eradication of viral reservoirs of infection. The principal means by which protective HLA class I molecules, such as HLA-B*27:05 and HLA-B*57:01, slow HIV disease progression is believed to be via the particular HIV-specific CD8+ T cell responses restricted by those alleles. We focus here on HLA-B*27:05, one of the best-characterized protective HLA molecules, and the closely related HLA-B*27:02, which differs by only 3 amino acids and which has not been well studied in relation to control of HIV infection. We show that HLA-B*27:02 is also protective against HIV disease progression, but the CD8+ T-cell immunodominance hierarchy of HLA-B*27:02 differs strikingly from that of HLA-B*27:05. These findings indicate that the immunodominant HLA-B*27:02-restricted Nef response adds to protection mediated by the Gag and Pol specificities that dominate anti-HIV CD8+ T-cell activity in HLA-B*27:05-positive subjects.


CD8+ T cell; HIV Gag; HIV Nef; HLA; HLA-B*27; human immunodeficiency virus

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center