Transmission of human immunodeficiency virus type 1 from a patient who developed AIDS to an elite suppressor

Abstract

Elite suppressors (ES) are untreated human immunodeficiency virus type 1 (HIV-1)-infected patients who maintain viral loads of <50 copies/ml. The mechanisms involved in this control of viral replication remain unclear. Prior studies suggested that these patients, as well as long-term nonprogressors, are infected with defective HIV-1 variants. Other reports have shown that the HLA-B*27 and -B*57 alleles are overrepresented in these patients, suggesting that host factors play a role in the control of viral replication. In order to distinguish between these hypotheses, we studied differences in viral isolates and immune responses of an HIV-1 transmission pair. While both patients are HLA-B*57 positive, the transmitter progressed to AIDS, whereas the recipient, who is also HLA-B*27 positive, is an ES. Isolates from both patients were replication competent and contained the T242N escape mutation in Gag, which is known to decrease viral fitness. While the acquisition of compensatory mutations occurred in isolates from the progressor, a superior HIV-specific CD8(+) T-cell response in the ES appears to have prevented viral replication and thus the evolution toward a more fit variant. In addition, CD8(+) T cells in the ES have selected for a rare mutation in an immunodominant HLA-B*27-restricted Gag epitope, which also has a negative impact on fitness. The results strongly suggest that through direct and indirect mechanisms, CD8(+) T cells in some ES control HIV-1 isolates are capable of causing profound immunosuppression.

FIG. 1.

Phylogenetic analysis of viral sequences obtained from ES9 and the progressor. Phylogenetic trees of env (A) and gag (B) are shown. Sequences amplified from replication-competent virus (circles), provirus (squares), and plasma (triangles) for ES9 (green) and the progressor (blue) are compared to the most homologous clade B env sequences (branches without symbols) in the Los Alamos database. Sequences from clade D (black squares) serve as an outgroup.

FIG. 2.

Tat sequences from ES9 and the progressor. The amino acid sequences of Tat from isolates obtained from ES9 and the progressor are compared to the consensus clade B sequence. The extra amino acid sequence where the stop codon (asterisk) normally occurs is highlighted.

FIG. 3.

Fitness of virus from ES9 and the progressor. (A) Growth kinetics of representative replication-competent isolates from ES9 (green) and the progressor (blue) are compared to laboratory strain Ba-L (black). (B and C) Relative fitness of pseudotype virus containing gag from ES9-2 (green) and P-10 (blue) (B), which is based on the green fluorescent protein (GFP) expression seen when the respective pseudotype viruses are used to infect Jurkat cells (C). SSC, side scatter. (D and E) Relative fitness of pseudotype virus containing Gag with the A163S (D) or the N271H (E) mutation (both shown in green) compared to that of wild-type (WT) Gag (black). Error bars represent standard errors of the means from three independent experiments.

FIG. 4.

Sequences of Gag from ES9 and the progressor. Epitopes and compensatory mutations are highlighted.

FIG. 5.

Sequence of the entire genome of representative replication-competent isolates from ES9 and the progressor. Epitopes targeted by ES9 (green) and the progressor (blue) are shaded. LTR, long terminal repeat.

FIG. 5.

Sequence of the entire genome of representative replication-competent isolates from ES9 and the progressor. Epitopes targeted by ES9 (green) and the progressor (blue) are shaded. LTR, long terminal repeat.

FIG. 5.

Sequence of the entire genome of representative replication-competent isolates from ES9 and the progressor. Epitopes targeted by ES9 (green) and the progressor (blue) are shaded. LTR, long terminal repeat.

FIG. 5.

Sequence of the entire genome of representative replication-competent isolates from ES9 and the progressor. Epitopes targeted by ES9 (green) and the progressor (blue) are shaded. LTR, long terminal repeat.

FIG. 5.

Sequence of the entire genome of representative replication-competent isolates from ES9 and the progressor. Epitopes targeted by ES9 (green) and the progressor (blue) are shaded. LTR, long terminal repeat.

FIG. 5.

Sequence of the entire genome of representative replication-competent isolates from ES9 and the progressor. Epitopes targeted by ES9 (green) and the progressor (blue) are shaded. LTR, long terminal repeat.

FIG. 6.

Responses to wild-type and mutant KK10 epitopes. (A) CD8⁺ IFN-γ responses to the wild-type KK10 epitope (black) versus peptide with the N271H mutation detected by ELISPOT (green). SFC, spot-forming cells. (B) Percentage of KK10-positive cells that secrete both IFN-γ and TNF-α in response to wild-type and mutant peptide. (C) Percentage of CD8⁺ T cells that are KK10 positive after 6 days of stimulation of PBMC with wild-type and mutant peptide at either 0.01 or 1.0 μg/ml. (D) Percentage of KK10 cells that have proliferated after stimulation with 0.01 μg/ml of wild-type or mutant peptide. FITC, fluorescein isothiocyanate.

FIG. 7.

Immune responses of ES9 and the progressor (P). (A and B) Replication of either Ba-L or P-10 in the presence or absence of autologous CD8⁺ T cells (A) or NK cells (B) from both patients. Error bars represent standard errors of the means from three independent experiments. (C) Titers of NAb to env clones obtained from ES9 (green) and the progressor (blue). IC50, 50% inhibitory concentration.