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Substitution at rt269 in Hepatitis B Virus Polymerase Is a Compensatory Mutation Associated with Multi-Drug Resistance

Authors
 Sung Hyun Ahn  ;  Doo Hyun Kim  ;  Ah Ram Lee  ;  Beom Kyung Kim  ;  Yong Kwang Park  ;  Eun-Sook Park  ;  Sang Hoon Ahn  ;  Gu-Choul Shin  ;  Soree Park  ;  Hong Seok Kang  ;  Jin-Kyu Rhee  ;  Sung-Il Yang  ;  Youhoon Chong  ;  Kyun Hwan Kim 
Citation
 PLOS ONE, Vol.10(8) : e0136728, 2015 
Journal Title
 PLOS ONE 
Issue Date
2015
MeSH
Adenine/analogs & derivatives ; Adenine/therapeutic use ; Amino Acid Substitution/genetics ; Antiviral Agents/therapeutic use* ; Arabinofuranosyluracil/analogs & derivatives ; Arabinofuranosyluracil/therapeutic use ; Cell Line, Tumor ; Drug Resistance, Multiple, Viral/genetics* ; Gene Products, pol/genetics* ; Guanine/analogs & derivatives ; Guanine/pharmacology ; Hepatitis B Surface Antigens/metabolism ; Hepatitis B e Antigens/metabolism ; Hepatitis B virus/drug effects* ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic/drug therapy ; Hepatitis B, Chronic/virology ; Humans ; Lamivudine/therapeutic use ; Microbial Sensitivity Tests ; Models, Molecular ; Organophosphonates/therapeutic use ; Tenofovir/therapeutic use ; Virus Replication/drug effects
Abstract
The emergence of compensatory mutations in the polymerase gene of drug resistant hepatitis B virus (HBV) is associated with treatment failure. We previously identified a multi-drug resistant HBV mutant, which displayed resistance towards lamivudine (LMV), clevudine (CLV), and entecavir (ETV), along with a strong replication capacity. The aim of this study was to identify the previously unknown compensatory mutations, and to determine the clinical relevance of this mutation during antiviral therapy. In vitro mutagenesis, drug susceptibility assay, and molecular modeling studies were performed. The rtL269I substitution conferred 2- to 7-fold higher replication capacity in the wild-type (WT) or YMDD mutation backbone, regardless of drug treatment. The rtL269I substitution alone did not confer resistance to LMV, ETV, adefovir (ADV), or tenofovir (TDF). However, upon combination with YMDD mutation, the replication capacity under LMV or ETV treatment was enhanced by several folds. Molecular modeling studies suggested that the rtL269I substitution affects template binding, which may eventually lead to the enhanced activity of rtI269-HBV polymerase in both WT virus and YMDD mutant. The clinical relevance of the rtL269I substitution was validated by its emergence in association with YMDD mutation in chronic hepatitis B (CHB) patients with sub-optimal response or treatment failure to LMV or CLV. Our study suggests that substitution at rt269 in HBV polymerase is associated with multi-drug resistance, which may serve as a novel compensatory mutation for replication-defective multi-drug resistant HBV.
Files in This Item:
T201503978.pdf Download
DOI
10.1371/journal.pone.0136728
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Beom Kyung(김범경) ORCID logo https://orcid.org/0000-0002-5363-2496
Ahn, Sang Hoon(안상훈) ORCID logo https://orcid.org/0000-0002-3629-4624
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/141529
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