HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors

Abstract

A unique cohort of HIV-1-infected long term nonprogressors (LTNP) with normal CD4(+) T cell counts and <50 copies/ml of plasma were prospectively recruited for study. HLA typing revealed a dramatic association between the HLA B*5701 class I allele and nonprogressive infection [85% (11 of 13) vs. 9.5% (19 of 200) in progressors; P < 0. 001]. Antigen-specific CD8(+) T cells were enumerated by flow cytometric detection of intracellular IFN-gamma in response to HIV antigens and HLA B*57-gag tetramer staining. No quantitative differences in the total HIV-specific CD8(+) T cell responses were observed between B*57(+) LTNP and five B*57(+) progressors (P = 0.4). Although similar frequencies of peptide specific CD8(+) T cells were also found, the gag-specific CD8(+) T cell response in the LTNP group was highly focused on peptides previously shown to be B*57-restricted. These findings indicate that, within this phenotypically and genotypically distinct cohort, a host immune factor is highly associated with restriction of virus replication and nonprogressive disease. They also strongly suggest a mechanism of virus specific immunity that directly operates through the B*5701 molecule. Further characterization of qualitative differences in the virus-specific responses that distinguish HLA B*57(+) LTNP from progressors may ultimately define mechanisms of effective immune mediated restriction of virus replication.

Figure 1

The percent of CD3⁺CD8⁺ that are CD69⁺IFN-γ⁺ in response to autologous B cells infected with HIV-vaccinia recombinants encoding the indicated gene product. Background activity against β-galactosidase has been subtracted from the percents shown.

Figure 2

The percent of CD3⁺CD8⁺ cells that are CD69⁺IFN-γ⁺ in response to autologous B cells pulsed with overlapping peptides spanning the gag protein are shown for three HLA B*57-positive LTNPs (patients 5, 7, and 8) and three HLA B*57-positive progressors (patients 101, 102, and 105). Peptides 15, 17, 23, and 30 contain previously described highly conserved HLA B*57-restricted epitopes shown here in bold (15-QMVHQAISPRTLNAWVKVVE, 17-EKAFSPEVIPMFSALSEGAT, 23-PRGSDIAGTTSTLQEQIGWM and 30-YKTRAEQASQEVKNWMTET). Peptides 1–13 include p17 sequences. The N-terminal sequences of gag beyond peptide 30 (amino acid 320) elicited weak responses and are not shown.

Figure 3

The percent of CD3⁺CD8⁺ cells of patient 7 that are CD69⁺IFN-γ⁺ in response to autologous and heterologous HIV_SF162-infected CD4⁺ T cell targets. Background activity against uninfected CD4⁺ T cells from each patient is included (left column).