AIDS-protective HLA-B*27/B*57 and chimpanzee MHC class I molecules target analogous conserved areas of HIV-1/SIVcpz

Abstract

In the absence of treatment, most HIV-1-infected humans develop AIDS. However, a minority are long-term nonprogressors, and resistance is associated with the presence of particular HLA-B*27/B*57 molecules. In contrast, most HIV-1-infected chimpanzees do not contract AIDS. In comparison with humans, chimpanzees experienced an ancient selective sweep affecting the MHC class I repertoire. We have determined the peptide-binding properties of frequent chimpanzee MHC class I molecules, and show that, like HLA-B*27/B*57, they target similar conserved areas of HIV-1/SIV(cpz). In addition, many animals appear to possess multiple molecules targeting various conserved areas of the HIV-1/SIV(cpz) Gag protein, a quantitative aspect of the immune response that may further minimize the chance of viral escape. The functional characteristics of the contemporary chimpanzee MHC repertoire suggest that the selective sweep was caused by a lentiviral pandemic.

Fig. 1.

Chimpanzee class I molecules clustered based on B- and F-pocket similarities. The B and F pocket of HLA-B*5701 are taken as consensus. A dash indicates identity to the consensus, an amino acid replacement is represented by the conventional one-letter code, and an asterisk indicates the position where the amino acid is unknown. The allele frequency (All. fr.) figures of the wild-caught founder population have been provided. Molecules depicted in light and dark brown are from chimpanzees of the Central and East African subspecies, respectively. Dark orange represents unreported peptide-binding motifs, whereas light orange highlights the motifs that are in agreement with data reported by another research team (23, 24). The binding motifs for HLA-B*2705 and -B*5701 as well as previously identified Patr-binding motifs are provided (–25, 43). ^aThe conventional one-letter code identifies the preferred, or in brackets the tolerated, residues at the corresponding positions. ^bPatr-B*2402 has an identical B and a similar F pocket (–TL-F—–) as Patr-B*2401. Binding motif shown is from Patr-B*2401. ^cMolecule present in West and East African subspecies. ^dMolecule present in West, Central, and East African subspecies. The # marks additional primary anchors.

Fig. 2.

Map of potential HIV-1 Gag CTL epitopes recognized by Patr class I molecules. The Gag sequence of HXB2 is taken as consensus, with the consensus of SIV_cpz above (http://www.hiv.lanl.gov). A lowercase letter in the SIV_cpz consensus indicates a variable position. HLA-B*27 and -B*57 CTL epitopes are marked in yellow and red, respectively. Potential 9-mer epitopes are indicated by an arrow, with the relevant Patr molecule(s) mentioned. Molecules marked in green indicate the predicted MHC/peptide combinations that are tested in peptide-binding studies. Molecules specific for Central (P.t. troglodytes, P.t.t.) or East African chimpanzees (P.t. schweinfurthii, P.t.s.) are indicated. The predicted binding affinities using the NetMHCpan 2.0 algorithm are indicated by ¹high, ²intermediate, or ³low. The arrows above the underscored Patr molecules indicate previously reported CTL epitopes (30). The two potential epitopes, HK9 and RL9, identified with the NetMHCpan 2.0 algorithm are marked in blue. The control peptide, NPPIPVGEI, is boxed. The box in the B57-TW10 epitope indicates covered variation (Fig. S2).

Fig. 3.

IC₅₀ (μM) values of the different competitor peptides tested for Patr-A*0301, -B*0101, -B*0301, and -B*0501. The IC₅₀ values in bold were determined from regression curves (Fig. S3) derived from pooled data from five individual experiments. For all other conceivable combinations, the IC₅₀ values were derived from pooled data from three individual experiments. Previously described CTL epitopes are underscored (30). The color codes of the peptides correspond to the colors in Fig. 2. SC, standardized competitor (a peptide similar to the biotin-labeled indicator peptide). An asterisk indicates a significantly higher or lower binding affinity than the SC.

Fig. 4.

Analysis of cellular immune responses in three chimpanzees belonging to an experimentally infected HIV-1 cohort. The peptides present in the Gag peptide pools are summarized in Fig. S4. A plus sign indicates that a CTL response to the Gag pool was observed, and the percentage-specific lysis is given in brackets (31). The Patr-A and -B molecules present on the haplotypes of chimpanzees Laurens, Zeef, and Thijs are given. The relevant MHC/peptide combinations that probably contribute to the previously observed Gag-pool-specific CTL responses are given, and the color codes of the peptides correspond to the colors in Fig. 2. Previously described CTL epitopes are underscored (30). A gray background indicates data obtained using only the NetMHCpan 2.0 algorithm. ^aAnimal is homozygous for this molecule.

Fig. 5.

MHC class I haplotypes of the founder chimpanzees. Molecules that bind conserved Gag peptides overlapping the areas targeted only by HLA-B*57 are presented in red, whereas orange indicates molecules binding peptides overlapping the areas targeted by HLA-B*27 and -B*57. Boxed molecules are predicted to bind HLA-B*27/B*57-like overlapping conserved Gag peptides based on the NetMHCpan 2.0 algorithm. NT indicates not typed, because data are no longer accessible.