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

Ellen M Leitman (1, 2) , Christian B Willberg (3) , Ming-Han Tsai (1) , Huabiao Chen (4, 5, 2) , Søren Buus (6) , Fabian Chen (7) , Lynn Riddell (8) , David Haas (9) , Jacques Fellay (10) , James J Goedert (11) , Alicja Piechocka-Trocha (4) , Bruce D Walker (4, 12) , Jeffrey N. Martin (13) , Steven G. Deeks (13) , Steven M Wolinsky (3, 14) , Jeremy Martinson (15) , Maureen P. Martin (16) , Ying Qi (16) , Asier Sáez-Cirión (17) , Otto O Yang (18) , Philippa C Matthews (3, 19) , Mary Carrington (16, 4) , Philip Jr Goulder (1, 12)

1 University of Oxford
2 HMS - Harvard Medical School [Boston]
3 Big Data Institute - Nuffield Department of Medicine [Oxford, UK]
4 Ragon Institute of MGH, MIT and Harvard
5 Massachusetts General Hospital [Boston]
6 UCPH - University of Copenhagen = Københavns Universitet
7 Royal Berkshire Hospital
8 NHS Foundation Trust [London]
9 Vanderbilt University School of Medicine [Nashville]
10 EPFL - Ecole Polytechnique Fédérale de Lausanne
11 NCI-NIH - National Cancer Institute [Bethesda]
12 UKZN - University of KwaZulu-Natal [Durban, Afrique du Sud]
13 UC San Francisco - University of California [San Francisco]
14 Northwestern University Feinberg School of Medicine
15 PITT - University of Pittsburgh
16 FNLCR - Frederick National Laboratory for Cancer Research
17 HIV, Inflammation et persistance - HIV, Inflammation and Persistence
18 UCLA - University of California [Los Angeles]
19 John Radcliffe Hospital [Oxford University Hospital]

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.

Mots clés: HLA-B*14; immune control; HIV; CD8+ T cells

Domaines: Sciences du Vivant [q-bio]; Immunologie

Ellen M Leitman, Christian B Willberg, Ming-Han Tsai, Huabiao Chen, Søren Buus, et al.. HLA-B*14:02-Restricted Env-Specific CD8+ T-Cell Activity Has Highly Potent Antiviral Efficacy Associated with Immune Control of HIV Infection. Journal of Virology, 2017, 91 (22), pp.e00544-17. ⟨10.1128/JVI.00544-17⟩. ⟨pasteur-02549962⟩