Multilayered HIV-1 gag-specific T-cell responses contribute to slow progression in HLA-A*30-B*13-C*06-positive patients.

Abstract

Objective:The HLA-A∗30-B∗13-C∗06 haplotype is reported to be associated with slow disease progression in the HIV-1-infected Northern Han Chinese population, but the mechanism remains unknown.Design:Gag-specific T-cell responses and gag sequencing were performed in nine B′ clade HIV-1-infected HLA-A∗30-B∗13-C∗06-positive slow progressors to understand HLA-associated viral control.Methods:Interferon-γ ELISPOT assays were performed to determine the Gag-specific T-cell responses and cross-reactivity to variant peptides. Longitudinal HIV-1 gag sequencing was performed at the clonal level.Results:The overlapping peptides (OLP)-48: RQANFLGKIWPSHKGRPGNF (RL42 Gag434-453); OLP-2: GQLDRWEKIRLRPGGKKKYR (RL42 Gag11-30); OLP-15: VQNLQGQMVHQPISPRTLNA (RL42 Gag135-154) and OLP-16: HQPISPRTLNAWVKVVEEKA (RL42 Gag144-163) were dominant in HLA-A∗30-B∗13-C∗06-positive patients. A new epitope [HQPISPRTL (Gag144-152, HL9)] within OLP-15 and OLP-16 was identified. Results showed that strong cross-reactive responses to multiple immunodominant peptides were associated with better clinical outcomes. In addition, efficient cross-recognition of HL9 autologous variants developed in patients was associated with high CD4+ T-cell counts. However, two patients who had developed mutations to their dominant responses during the follow-up experienced decrease in CD4+ T-cell counts. It appears that Gag-specific T-cell responses against one or more unmutated epitopes or cross-recognition of autologous epitope variants contribute to slow disease progression in HLA-A∗30-B∗13-C∗06-positive patients.Conclusion:We conclude that a single ‘appropriate’ Gag-specific T-cell response appears to be sufficient to protect patients from disease progression. HLA-A∗30-B∗13-C∗06-positive individuals benefited from having a choice of numerous immunodominant gag epitopes for T cells to react. The study offers new insight for future design of T-cell-based HIV-1 vaccine.