Two MHC class I molecules associated with elite control of immunodeficiency virus replication, Mamu-B*08 and HLA-B*2705, bind peptides with sequence similarity

Abstract

HLA-B27- and -B57-positive HIV-infected humans have long been associated with control of HIV replication, implying that CD8(+) T cell responses contribute to control of viral replication. In a similar fashion, 50% of Mamu-B*08-positive Indian rhesus macaques control SIVmac239 replication and become elite controllers with chronic-phase viremia <1000 viral RNA copies/ml. Interestingly, Mamu-B*08-restricted SIV-derived epitopes appeared to match the peptide binding profile for HLA-B*2705 in humans. We therefore defined a detailed peptide-binding motif for Mamu-B*08 and investigated binding similarities between the macaque and human MHC class I molecules. Analysis of a panel of approximately 900 peptides revealed that despite substantial sequence differences between Mamu-B*08 and HLA-B*2705, the peptide-binding repertoires of these two MHC class I molecules share a remarkable degree of overlap. Detailed knowledge of the Mamu-B*08 peptide-binding motif enabled us to identify six additional novel Mamu-B*08-restricted SIV-specific CD8(+) T cell immune responses directed against epitopes in Gag, Vpr, and Env. All 13 Mamu-B*08-restricted epitopes contain an R at the position 2 primary anchor and 10 also possess either R or K at the N terminus. Such dibasic peptides are less prone to cellular degradation. This work highlights the relevance of the Mamu-B*08-positive SIV-infected Indian rhesus macaque as a model to examine elite control of immunodeficiency virus replication. The remarkable similarity of the peptide-binding motifs and repertoires for Mamu-B*08 and HLA-B*2705 suggests that the nature of the peptide bound by the MHC class I molecule may play an important role in control of immunodeficiency virus replication.

Figure 1

Comparison of the α1 and α2 domains of the MHC class I alleles, Mamu-B*08, Mamu-B*03, and HLA-B*2705. Residues matching the sequence of Mamu-B*08 are indicated by dots (.). Residues predicted to form the B and F binding pockets are indicated based on previous studies (–76).

Figure 2

Similarity of primary and secondary anchor positions between Mamu-B*08, Mamu-B*03, and HLA-B*2705. Primary and secondary anchor positions were defined using the PSCL matrix data (Table II and Supplemental Table II), as described in the Materials and Methods. Primary anchor positions are identified by bold font and blue shading. Dominant secondary positions are indicated by bold font and green shading, while weak secondary positions are highlighted by orange shading. Also shown are the most preferred residues at the corresponding position. In the case of the primary anchors, residues associated with an ARB >0.1 are shown. At secondary positions, residues with an ARB >0.3 are shown.

Figure 3

Ex vivo whole PBMC IFN-γ ELISPOT results of Mamu-B*08-restricted minimal optimal CD8⁺ T-cell epitopes. Freshly isolated PBMC from seven Mamu-B*08-positive SIV-infected macaques were tested with Mamu-B*08 binding peptides in IFN-γ ELISPOT assays. Animals were tested during the chronic phase of SIV infection (>35 weeks post-SIV infection). Results shown represent the 13 SIVmac239 epitopes known to be restricted by Mamu-B*08. Mean values and SDs from triplicate wells were calculated for each assay. Background (the mean of wells without peptide) levels were subtracted from each well. Mean responses <50 SFC per 1 × 10⁶ PBMC were not considered positive. Assay results are shown as SFC per 1 × 10⁶ PBMC. Nef RL9* refers to the epitope at positions 8–16 in Nef, while Nef RL9 refers to the Nef epitope at positions 246–254. The SDs of Nef RL10 in r02019 (1,522 SFC/10⁶ PBMC) and Nef RL10 in r99006 (1,753 SFC/10⁶ PBMC) were 197 and 140, respectively.