Differential Immunodominance Hierarchy of CD8 + T-Cell Responses in HLA-B27:05- and -B27:02-Mediated Control of HIV-1 Infection

• Published in: Journal of virology Vol. 92; no. 4
• Main Authors: Adland, Emily, Hill, Matilda, Lavandier, Nora, Csala, Anna, Edwards, Anne, Chen, Fabian, Radkowski, Marek, Kowalska, Justyna D, Paraskevis, Dimitrios, Hatzakis, Angelos, Valenzuela-Ponce, Humberto, Pfafferott, Katja, Williams, Ian, Pellegrino, Pierre, Borrow, Persephone, Mori, Masahiko, Rockstroh, Jürgen, Prado, Julia G, Mothe, Beatriz, Dalmau, Judith, Martinez-Picado, Javier, Tudor-Williams, Gareth, Frater, John, Stryhn, Anette, Buus, Soren, Teran, Gustavo Reyes, Mallal, Simon, John, Mina, Buchbinder, Susan, Kirk, Gregory, Martin, Jeffrey, Michael, Nelson, Fellay, Jacques, Deeks, Steve, Walker, Bruce, Avila-Rios, Santiago, Cole, David, Brander, Christian, Carrington, Mary, Goulder, Philip
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 15.02.2018
• Subjects: CD8-Positive T-Lymphocytes - immunology; Cellular Response to Infection; gag Gene Products, Human Immunodeficiency Virus - genetics; Genes, MHC Class I; HIV Infections - immunology; HIV Infections - virology; HIV-1; HLA-B27 Antigen - genetics; Humans; Immunodominant Epitopes - immunology; nef Gene Products, Human Immunodeficiency Virus - genetics; Viral Load; human immunodeficiency virus; HIV Nef; HLA; CD8+ T cell; HLA-B27; HIV Gag
• ISSN: 0022-538X; 1098-5514; 1098-5514
• DOI: 10.1128/JVI.01685-17

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 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 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 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 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 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. 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-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 specificities that dominate anti-HIV CD8 T-cell activity in HLA-B*27:05-positive subjects.