期刊
JOURNAL OF VIROLOGY
卷 92, 期 4, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01685-17
关键词
CD8(+) T cell; HIV Gag; HIV Nef; HLA; HLA-B*27; human immunodeficiency virus
类别
资金
- National Institutes of Health [RO1AI46995]
- Wellcome Trust [WT104748MA]
- Frederick National Laboratory for Cancer Research [HHSN261200800001E]
- Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research
- National Institute of Allergy and Infectious Diseases (NIAID) [U01-AI35042, U01-AI35039, U01-AI35040, U01-AI35041, UM1-AI35043]
- UCSF/Gladstone Institute of Virology and Immunology CFAR [P30 AI027763]
- CFAR Network of Integrated Systems [R24 AI067039]
- Delaney AIDS Research Enterprise (DARE) [AI096109, A127966]
- amfAR Institute for HIV Cure Research [amfAR 109301]
- MRC [MR/K012037]
- MRC [MR/L006588/1, MR/K012037/1] Funding Source: UKRI
- Medical Research Council [MR/K012037/1, MR/L006588/1] Funding Source: researchfish
- NATIONAL CANCER INSTITUTE [ZIABC010792, ZIABC010791] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U01AI035042, P30AI027763, UM1AI035043, U01AI035039, U19AI096109, R01AI046995, U01AI035041, R24AI067039, U01AI035040] Funding Source: NIH RePORTER
The well- characterized association between HLA-B*27:05 and protection against HIV disease progression has been linked to immunodominant HLA-B*27:05restricted 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 HLAB* 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 HLAB* 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 HLAB* 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 specif(icities that dominate anti-HIV CD8(+) T-cell activity in HLA-B*27:05- positive subjects.
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