5E00

Structure of HLA-A2 P130

Summary for 5E00

• Entry DOI: 10.2210/pdb5e00/pdb
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, GLY-VAL-TRP-ILE-ARG-THR-PRO-PRO-ALA, ... (5 entities in total)
• Functional Keywords: hla, mhc, hbv, hbc, t cell, escape, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 44826.79

Authors

Zhang, Y.,Wu, Y.,Qi, J.,Liu, J.,Gao, G.F.,Meng, S. (deposition date: 2015-09-26, release date: 2017-01-18, Last modification date: 2019-01-23)

Primary citation

Zhang, Y.,Wu, Y.,Deng, M.,Xu, D.,Li, X.,Xu, Z.,Hu, J.,Zhang, H.,Liu, K.,Zhao, Y.,Gao, F.,Bi, S.,Gao, G.F.,Zhao, J.,Liu, W.J.,Meng, S.
CD8+T-Cell Response-Associated Evolution of Hepatitis B Virus Core Protein and Disease Progress.
J. Virol., 92:-, 2018

PubMed Abstract: Under the immune pressure of cytotoxic T cells (CTLs), hepatitis B virus (HBV) evolves to accumulate mutations more likely within epitopes to evade immune detection. However, little is known about the specific patterns of the immune pressure-associated HBV mutation of T-cell epitopes and their link to disease progression. Here, we observed a correlation of the accumulated variants on HBV core protein (HBc) with the disease severity of HBV infection. Further analysis indicated that these substitutions were mostly located within CD8 T-cell epitopes of HBc protein, which were systematically screened and identified in an unbiased manner in our study. From individual peptide level to the human leukocyte antigen I (HLA-I)-restricted population level, we elucidated that the mutations in these well-defined HLA-I-restricted T-cell epitopes significantly decreased antiviral activity-specific CTLs and were positively associated with clinical parameters and disease progression in HBV-infected patients. The molecular pattern for viral epitope variations based on the sequencing of 105 HBV virus genomes indicated that the C-terminal portion (Pc), especially the Pc-1 and Pc-2 positions, have the highest mutation rates. Further structural analysis of HLA-A*02 complexed to diverse CD8 T-cell epitopes revealed that the highly variable C-terminal bulged peak of M-shaped HBc-derived epitopes are solvent exposed, and most of the CDR3βs of the T-cell receptor hover over them. These data shed light on the molecular and immunological mechanisms of T-cell immunity-associated viral evolution in hepatitis B progression, which is beneficial for designing immunotherapies and vaccines. The specific patterns of sequence polymorphisms of T-cell epitopes and the immune mechanisms of the HBV epitope mutation-linked disease progression are largely unclear. In this study, we systematically evaluated the contribution of CD8 T cells to the disease progress-associated evolution of HBV. By evaluation of patient T-cell responses based on the peptide repertoire, we comprehensively characterized the association of clinical parameters in chronic hepatitis B with the antiviral T-cell response-associated mutations of the viruses from the single-epitope level to the overall HLA-I-restricted peptide levels. Furthermore, we investigated the molecular basis of the HLA-A2-restricted peptide immune escape and found that the solvent-exposed C-terminal portion of the epitopes is highly variable under CDR3β recognition. Our work may provide a comprehensive evaluation of viral mutations impacted by the host CTL response in HBV disease progression in the context of the full repertoire of HBc-derived epitopes.

PubMed: 29950410
DOI: 10.1128/JVI.02120-17

Experimental method

X-RAY DIFFRACTION (1.7 Å)