Influence of dominant HIV-1 epitopes on HLA-A3/peptide complex formation

Abstract

The binding of peptides to MHC class I molecules induces MHC/ peptide complexes that have specific conformational features. Little is known about the molecular and structural bases required for an optimal MHC/peptide association able to induce a dominant T cell response. We sought to characterize the interaction between purified HLA-A3 molecules and four well known CD8 epitopes from HIV-1 proteins. To define the characteristics of HLA-peptide complex formation and to identify potential structural changes, we used biochemical assays that detect well formed complexes. We tested the amplitude, stability, and kinetic parameters of the interaction between HLA-A3, peptides, and anti-HLA mAbs. Our results show that the four epitopes Nef73-82, Pol325-333, Env37-46, and Gag20 -28 bind strongly to HLA-A3 molecules and form very stable complexes that are detected with differential patterns of mAb reactivity. The most striking result is the nonrecognition of the HLA-A3/Gag20 -28 complex by the A11.1M mAb specific to HLA-A3/-A11 alleles. To explain this observation, from the data published on HLA-A11 crystallographic structure, we propose molecular models of the HLA-A3 molecule complexed with Nef73-82, Pol325-333, and Gag20 -28 epitopes. In the HLA-A3/Gag20 -28 complex, we suggest that Arg at position P1 of the peptide may push the ␣2 helix residue Trp-167 of HLA-A3 and affect mAb recognition. Such observations may have great implications for T cell antigen receptor recognition and the immunogenicity of HLA/ peptide complexes. C rystallographic structure analysis of a series of class I MHC/peptide complexes revealed that peptides carrying specific MHC anchor residues bind in a large-solvent-exposed groove of the heavy chain. This binding groove consists of two long helices, ␣1 and ␣2, mounted on a floor of eight antiparallel ␤-strands. Polymorphic residues in the groove determine distinct binding pockets from A to F. Bound peptides adopt extended conformations that stretch from the N-to the C-terminal end of the groove, and their anchor residues, generally at positions P2 and P9/10, interact with pockets B and F, respectively (1-4). In most MHC complexes, peptides are partly buried in the binding site, and only a few side chains of the peptide pointing away from the groove toward the solvent are accessible for CD8 T cell recognition (1, 5).The impact of peptide binding on heavy-chain MHC conformation can be detected serologically by the observation of differential anti-MHC mAbs reactivities. This effect has been mainly documented with murine anti-H2-K b , -K d , and -L d mAbs by testing the expression on mutant cells of class I MHC molecules loaded with synthetic peptides or by performing selective immunoprecipitation of complexes containing different sets of peptide. In those studies, specific residues of the bound peptide essential for mAb recognition were identified, and the impact of exposed, but also buried, peptide residues on ␣1 and ␣2 MHC conformation was demonstrated (6-12). The same effect of peptides on mAb recogn...

Sequence- and Interactome-Based Prediction of Viral Protein Hotspots Targeting Host Proteins: A Case Study for HIV Nef

“…However, Nef peptides most frequently recognized by T cells of HIV-1-infected individuals were shown to be along 90–97, 135–143, 71–81, 77–85, 90–100, 73–82, and 128–137 [43] , closely matching our predicted hotspots. In fact, as predicted in our computations, the HIV Nef 73–82 epitope was previously shown to bind strongly to HLA-A3 molecules [44] . The high immunogenetic property of the HIV Nef core region is reflected by the relative stability of the Nef sequence in this region [45] .…”

Frequency of HLA-A*03 associates with HIV-1 infection in a Chinese cohort

“…Furthermore, the number of HIV-negative FBDs in this study was limited compared with the infected subjects. Taking into account a large number of HLA-A3-restricted HIV-1 epitopes have been reported and the mechanism of T cell receptor cross-recognition of these epitopes has been thoroughly examined [25,26], the potential protective function of HLA-A*03 is worthy of further study.…”

中国前献血人群中hla-A*03与hiv-1感染关系的研究

“…本研究募集的安徽省阜阳县农村居民 不同种族中的分布不同以及研究募集的 HIV 对照组 的 前 献 血 者 数 量 较 少 的 限 制 . 有 报 道 实 验 证 实 HLA-A*03 可以呈递的多种 HIV 抗原表位, 并对 T 细 胞对这些表位的交叉识别进行了深入研究 [25,26] . 这 些结果都提示 HLA-A*03 对 HIV 感染的潜在的保护 作用值得进一步研究.…”