title: HBV quasispecies composition in Lamivudine-failed chronic hepatitis B patients and its influence on virological response to Tenofovir-based rescue therapy.
abstract: The present study sought to evaluate the structure of HBV quasispecies in Lamivudine (LMV)-failed chronic hepatitis B (CHB) patients and its impact in defining the subsequent virological responses to Tenofovir (TDF)-based rescue-therapy. By analyzing HBV clones encompassing reverse transcriptase (RT) and surface (S) region from LMV-failed and treatment-naïve CHB patients, we identified 5 classical and 12 novel substitutions in HBV/RT and 9 substitutions in immune-epitopes of HBV/S that were significantly associated with LMV failure. In silico analysis showed spatial proximity of some of the newly-identified, mutated RT residues to the RT catalytic centre while most S-substitutions caused alteration in epitope hydrophobicity. TDF administration resulted in virological response in 60% of LMV-failed patients at 24-week but non-response in 40% of patients even after 48-weeks. Significantly high frequencies of 6 S-substitutions and one novel RT-substitution, rtH124N with 6.5-fold-reduced susceptibility to TDF in vitro, were noted at baseline in TDF non-responders than responders. Follow-up studies depicted greater evolutionary drift of HBV quasispecies and significant decline in frequencies of 3 RT and 6 S-substitutions in responder-subgroup after 24-week TDF-therapy while most variants persisted in non-responders. Thus, we identified the HBV-RT/S variants that could potentially predict unfavorable response to LMV/TDF-therapy and impede immune-mediated viral clearance.
authors.affiliation: Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Banerjee
authors.affiliation: Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chakraborty
authors.affiliation: Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: Rajiv Kumar
authors.initials: RK
authors.lastname: Mondal
authors.affiliation: Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: Mousumi
authors.initials: M
authors.lastname: Khatun
authors.affiliation: Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: Somenath
authors.initials: S
authors.lastname: Datta
authors.affiliation: Department of Hepatology, School of Digestive &Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: Kausik
authors.initials: K
authors.lastname: Das
authors.affiliation: Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: Pratap
authors.initials: P
authors.lastname: Pandit
authors.affiliation: BioMedical Genomics Centre, National Institute of Biomedical Genomics, West Bengal, India.
authors.forename: Souvik
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: Soma
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Saikat
authors.initials: S
authors.lastname: Chakrabarti
authors.affiliation: Department of Hepatology, School of Digestive &Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chowdhury
authors.affiliation: Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: Simanti
authors.initials: S
authors.lastname: Datta
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D060965:Clonal Evolution; D003710:Demography; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D005814:Genes, Viral; D005838:Genotype; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use*; D009154:Mutation / Q000235:genetics; D000072417:Protein Domains; D000074704:Quasispecies; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry; D000068698:Tenofovir / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D018985:Epitopes, B-Lymphocyte; D014764:Viral Proteins; D019259:Lamivudine; D000068698:Tenofovir; D012194:RNA-Directed DNA Polymerase