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Differential Immunodominance Hierarchy of CD8T-Cell Responses in HLA-B*27:05- and -B*27:02-Mediated Control of HIV-1 Infection.

Differential Immunodominance Hierarchy of CD8T-Cell Responses in HLA-B*27:05- and -B*27:02-Mediated Control of HIV-1 Infection.
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Adland E, Hill M, Lavandier N, Csala A, Edwards A, Chen F, Radkowski M, Kowalska JD, Paraskevis D, Hatzakis A, Valenzuela-Ponce H, Pfafferott K, Williams I, Pellegrino P, Borrow P, Mori M, Rockstroh J, Prado JG, Mothe B, Dalmau J, Martinez-Picado J, Tudor-Williams G, Frater J, Stryhn A, Buus S, Teran GR, Mallal S, John M, Buchbinder S, Kirk G, Martin J, Michael N, Fellay J, Deeks S, Walker B, Avila-Rios S, Cole D, Brander C, Carrington M, Goulder P,


Adland E, Hill M, Lavandier N, Csala A, Edwards A, Chen F, Radkowski M, Kowalska JD, Paraskevis D, Hatzakis A, Valenzuela-Ponce H, Pfafferott K, Williams I, Pellegrino P, Borrow P, Mori M, Rockstroh J, Prado JG, Mothe B, Dalmau J, Martinez-Picado J, Tudor-Williams G, Frater J, Stryhn A, Buus S, Teran GR, Mallal S, John M, Buchbinder S, Kirk G, Martin J, Michael N, Fellay J, Deeks S, Walker B, Avila-Rios S, Cole D, Brander C, Carrington M, Goulder P, (click to view)

Adland E, Hill M, Lavandier N, Csala A, Edwards A, Chen F, Radkowski M, Kowalska JD, Paraskevis D, Hatzakis A, Valenzuela-Ponce H, Pfafferott K, Williams I, Pellegrino P, Borrow P, Mori M, Rockstroh J, Prado JG, Mothe B, Dalmau J, Martinez-Picado J, Tudor-Williams G, Frater J, Stryhn A, Buus S, Teran GR, Mallal S, John M, Buchbinder S, Kirk G, Martin J, Michael N, Fellay J, Deeks S, Walker B, Avila-Rios S, Cole D, Brander C, Carrington M, Goulder P,

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Journal of virology 2018 01 3092(4) pii 10.1128/JVI.01685-17

Abstract

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 CD8T-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 CD8T-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 CD8T-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 CD8T-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 CD8T-cell responses that dominate HIV-specific CD8T-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.CD8T 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 CD8T 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 CD8T-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 CD8T-cell activity in HLA-B*27:05-positive subjects.

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