PMID- 29950410 OWN - NLM STAT- MEDLINE DCOM- 20180827 LR - 20220330 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 92 IP - 17 DP - 2018 Sep 1 TI - CD8(+) T-Cell Response-Associated Evolution of Hepatitis B Virus Core Protein and Disease Progress. LID - 10.1128/JVI.02120-17 [doi] LID - e02120-17 AB - 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 CDR3betas 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.IMPORTANCE 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 CDR3beta 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. CI - Copyright (c) 2018 American Society for Microbiology. FAU - Zhang, Yu AU - Zhang Y AD - CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. AD - Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China. FAU - Wu, Yan AU - Wu Y AD - Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China. FAU - Deng, Mengmeng AU - Deng M AD - CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. FAU - Xu, Dongping AU - Xu D AD - Research Center for Clinical and Translational Medicine/Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China. FAU - Li, Xiaodong AU - Li X AD - Research Center for Clinical and Translational Medicine/Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China. FAU - Xu, Zhihui AU - Xu Z AD - Research Center for Clinical and Translational Medicine/Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China. FAU - Hu, Jun AU - Hu J AD - CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. FAU - Zhang, Han AU - Zhang H AD - CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. FAU - Liu, Kefang AU - Liu K AD - NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. FAU - Zhao, Yingze AU - Zhao Y AD - NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. FAU - Gao, Feng AU - Gao F AD - Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China. FAU - Bi, Shengli AU - Bi S AD - NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. FAU - Gao, George F AU - Gao GF AD - CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. AD - Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China. AD - NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. AD - Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen, China. FAU - Zhao, Jingmin AU - Zhao J AD - Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China. FAU - Liu, William J AU - Liu WJ AD - NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China liujun@ivdc.chinacdc.cn mengsd@im.ac.cn. AD - Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen, China. FAU - Meng, Songdong AU - Meng S AD - CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China liujun@ivdc.chinacdc.cn mengsd@im.ac.cn. AD - University of Chinese Academy of Sciences, Beijing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180816 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (Hepatitis B Core Antigens) SB - IM MH - Epitopes, T-Lymphocyte/genetics/*immunology MH - *Evolution, Molecular MH - Hepatitis B Core Antigens/genetics/*immunology MH - Hepatitis B, Chronic/*immunology/*pathology/virology MH - Humans MH - Mutation MH - Selection, Genetic MH - Sequence Analysis, DNA MH - T-Lymphocytes/*immunology PMC - PMC6096822 OTO - NOTNLM OT - HLA-A2 OT - chronic hepatitis B OT - epitope variation pattern OT - immunopathogenesis OT - viral fitness EDAT- 2018/06/29 06:00 MHDA- 2018/08/28 06:00 PMCR- 2019/02/16 CRDT- 2018/06/29 06:00 PHST- 2017/12/11 00:00 [received] PHST- 2018/06/05 00:00 [accepted] PHST- 2018/06/29 06:00 [pubmed] PHST- 2018/08/28 06:00 [medline] PHST- 2018/06/29 06:00 [entrez] PHST- 2019/02/16 00:00 [pmc-release] AID - JVI.02120-17 [pii] AID - 02120-17 [pii] AID - 10.1128/JVI.02120-17 [doi] PST - epublish SO - J Virol. 2018 Aug 16;92(17):e02120-17. doi: 10.1128/JVI.02120-17. Print 2018 Sep 1.