title: Composition and Interactions of Hepatitis B Virus Quasispecies Defined the Virological Response During Telbivudine Therapy.
abstract: Reverse transcriptase (RT) mutations contribute to hepatitis B virus resistance during antiviral therapy with nucleos(t)ide analogs. However, the composition of the RT quasispecies and their interactions during antiviral treatment have not yet been thoroughly defined. In this report, 10 patients from each of 3 different virological response groups, i.e., complete virological response, partial virological response and virological breakthrough, were selected from a multicenter trial of Telbivudine treatment. Variations in the drug resistance-related critical RT regions in 107 serial serum samples from the 30 patients were examined by ultra-deep sequencing. A total of 496,577 sequence reads were obtained, with an average sequencing coverage of 4,641X per sample. The phylogenies of the quasispecies revealed the independent origins of two critical quasispecies, i.e., the rtA181T and rtM204I mutants. Data analyses and theoretical modeling showed a cooperative-competitive interplay among the quasispecies. In particular, rtM204I mutants compete against other quasispecies, which eventually leads to virological breakthrough. However, in the absence of rtM204I mutants, synergistic growth of the drug-resistant rtA181T mutants with the wild-type quasispecies could drive the composition of the viral population into a state of partial virological response. Furthermore, we demonstrated that the frequency of drug-resistant mutations in the early phase of treatment is important for predicting the virological response to antiviral therapy.
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Dong
authors.affiliation: CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology; CAS Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology; Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yungang
authors.initials: Y
authors.lastname: He
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.|Shanghai Shenyou Biotechnology Co., Ltd., Shanghai, China.
authors.forename: Weirong
authors.initials: W
authors.lastname: Jin
authors.affiliation: Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Fan
authors.affiliation: CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology; CAS Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology; Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Minxian
authors.initials: M
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology; CAS Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology; Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Li
authors.affiliation: Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Yangyi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai Shenyou Biotechnology Co., Ltd., Shanghai, China.
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Xie
authors.affiliation: Shanghai Shenyou Biotechnology Co., Ltd., Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology; CAS Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology; Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Shengyue
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Fengming
authors.initials: F
authors.lastname: Lu
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Jidong
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhuang
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Locarnini
authors.affiliation: Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.|CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology; CAS Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology; Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Department of Microbiology and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.|State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences; Key Laboratory of Medical Molecular Virology affiliated to the Ministries of Education and Health, Shanghai Medical College and Department of Microbiology, School of Life Sciences; Fudan University, Shanghai, China.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology; CAS Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology; Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences; Key Laboratory of Medical Molecular Virology affiliated to the Ministries of Education and Health, Shanghai Medical College and Department of Microbiology, School of Life Sciences; Fudan University, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
authors.forename: Jinlin
authors.initials: J
authors.lastname: Hou
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood / Q000737:chemistry; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000145:classification / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010802:Phylogeny; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D012074:Remission Induction; D017422:Sequence Analysis, DNA; D000077712:Telbivudine; D013936:Thymidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D000077712:Telbivudine; D012194:RNA-Directed DNA Polymerase; D013936:Thymidine