HLA-B*14:02-Restricted Env-Specific CD8+ T-Cell Activity Has Highly Potent Antiviral Efficacy Associated with Immune Control of HIV Infection.
J Virol
; 91(22)2017 11 15.
Article
em En
| MEDLINE
| ID: mdl-28878089
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, 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*1402 and not to HLA-B*1401. Furthermore, the HLA-B*14-associated protection against HIV disease progression is significantly greater for HLA-B*1402 than for HLA-B*1401, 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*1402, and not HLA-B*1401. This reflects the increased functional avidity of the Env response over Gag, substantially more marked for HLA-B*1402. Finally, we show that HLA-B*1402 is significantly more strongly associated with viremic control than HLA-B*1401. 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Infecções por HIV
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HIV-1
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Proteína gp160 do Envelope de HIV
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Produtos do Gene gag do Vírus da Imunodeficiência Humana
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Antígeno HLA-B14
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Imunidade Celular
Tipo de estudo:
Clinical_trials
/
Risk_factors_studies
Limite:
Adult
/
Humans
Idioma:
En
Revista:
J Virol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Reino Unido