DIFFERENTIAL IMMUNODOMINANCE HIERARCHY OF CD8+ T CELL RESPONSES IN HLA-B*27:05 AND B*27:02-MEDIATED CONTROL OF HIV-1 INFECTION.
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., Reyes Teran G., 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.
The well-characterised 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 towards the conserved Gag 263-272 ('KK10') and Pol 901-909 'KY9' epitopes. We here 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 associate with slower disease progression and lower viral loads. The effect of HLA-B*27:02 appears 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 142-150, '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 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-characterised '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.