Control of human immunodeficiency virus type 1 is associated with HLA-B*13 and targeting of multiple gag-specific CD8+ T-cell epitopes

Abstract

To better understand relationships between CD8+ T-cell specificity and the immune control of human immunodeficiency virus type 1 (HIV-1), we analyzed the role of HLA-B*13, an allele associated with low viremia, in a cohort of 578 C clade-infected individuals in Durban, South Africa. Six novel B*13-restricted cytotoxic T lymphocyte epitopes were defined from analyses of 37 B*13-positive subjects, including three Gag epitopes. These B*13-restricted epitopes contribute to a broad Gag-specific CD8+ response that is associated with the control of viremia. These data are consistent with data from studies of other HLA-class I alleles associated with HIV control that have shown that the targeting of multiple Gag epitopes is associated with relative suppression of viremia.

FIG. 1.

Definition and optimization of six HLA-B*1302 epitopes. HLA restriction in each case was determined using intracellular IFN-γ-staining assays, as previously described (14). The HLA types on the y axis correspond to the Epstein-Barr virus transformed B-cell lines used as antigen-presenting cells. These match the HLA type of the effectors from subject 9308024 (HLA type, A*0301/3001, B*1302/1402, Cw*0602/0802). Epitope optimization was determined by IFN-γ enzyme-linked immunospot assays (14). (A to D) Epitopes from B and C clade-infected individuals. (E and F) Epitopes from B clade-infected individuals only. (A) Epitope VQNLQGQMV (Gag residues 135 to 143). (B) Epitope GQMREPRGSDI (Gag residues 226 to 236). (C) Epitope RQANFLGKI (Gag residues 429 to 437). (D) Epitope RQDILDLWV (Nef residues 106 to 114). (E) Epitope RQYDQILIEI (Pol residues 113 to 122). (F) Epitope GQGQWTYQI (Pol residues 488 to 496). SFC, spot-forming cells; PBMC, peripheral blood mononuclear cells.

FIG. 2.

Confirmation of the predicted motif for B*1302 with six defined epitopes and one predicted epitope. The B*1302 motif is inferred for position 2 and the carboxy terminus (PC) of the epitope.

FIG. 3.

Comparison of numbers of p17, p24, and p15 Gag responses to viral load. (A to C) Results for B*13-positive individuals (black and gray symbols represent clade B- and C-infected individuals, respectively). (D to F) Results for whole cohort of 578 individuals. (G) Association of ≤1 and ≥2 p17, p24, and p15 Gag responses to viral load for HLA-B*13-infected individuals.

FIG. 4.

Mutations in Gag associated with HLA-B*13. (A) Comparisons of numbers of variations from the consensus for p24 VQNLQGQMV (Gag residues 135 to 143; numbering corresponds to that for the HXB2 reference strain) with those for five residues beyond the N and C termini of the epitope. A total of 562 C clade RNA and DNA sequences were compared. Comparisons were also made for subjects not carrying B*57/5801. (B) Comparisons of numbers of variations from the consensus for p15 RQANFLGKI (Gag residues 429 to 437; numbering corresponds to that for the HXB2 reference strain) with those for five residues beyond the N and C termini of the epitope. A total of 347 C clade RNA and DNA sequences were compared. (C) Three epitopes restricted by B*13, B*1510, and B*57/5801 and their relations to the mutation at position 146, which is significantly associated with B*13, B*1510, and B*57/5801, and to the mutation at position 147, which is significantly associated with B*13 and B*57/5801 (shaded residues). +ve, positive; −ve, negative; WT, wild type.