Substitution at rt269 in hepatitis B virus polymerase is a compensatory mutation associated with multi-drug resistance

Sung Hyun Ahn, Doo Hyun Kim, Ah Ram Lee, Beom Kyung Kim, Yong Kwang Park, Eun Sook Park, SangHoon Ahn, Gu Choul Shin, Soree Park, Hong Seok Kang, Jin Kyu Rhee, Sung Il Yang, Youhoon Chong, Kyun Hwan Kim

Research output: Contribution to journalArticle

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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 multidrug resistant HBV.

Original languageEnglish
Article numbere0136728
JournalPLoS One
Volume10
Issue number8
DOIs
Publication statusPublished - 2015 Aug 31

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Hepatitis B virus
multiple drug resistance
Multiple Drug Resistance
Viruses
Substitution reactions
Lamivudine
mutation
Mutation
Pharmaceutical Preparations
Molecular modeling
Tenofovir
Treatment Failure
drugs
Drug therapy
Mutagenesis
chronic hepatitis B
mutants
Chronic Hepatitis B
Antiviral Agents
Assays

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Ahn, S. H., Kim, D. H., Lee, A. R., Kim, B. K., Park, Y. K., Park, E. S., ... Kim, K. H. (2015). Substitution at rt269 in hepatitis B virus polymerase is a compensatory mutation associated with multi-drug resistance. PLoS One, 10(8), [e0136728]. https://doi.org/10.1371/journal.pone.0136728
Ahn, Sung Hyun ; Kim, Doo Hyun ; Lee, Ah Ram ; Kim, Beom Kyung ; Park, Yong Kwang ; Park, Eun Sook ; Ahn, SangHoon ; Shin, Gu Choul ; Park, Soree ; Kang, Hong Seok ; Rhee, Jin Kyu ; Yang, Sung Il ; Chong, Youhoon ; Kim, Kyun Hwan. / Substitution at rt269 in hepatitis B virus polymerase is a compensatory mutation associated with multi-drug resistance. In: PLoS One. 2015 ; Vol. 10, No. 8.
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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 multidrug resistant HBV.",
author = "Ahn, {Sung Hyun} and Kim, {Doo Hyun} and Lee, {Ah Ram} and Kim, {Beom Kyung} and Park, {Yong Kwang} and Park, {Eun Sook} and SangHoon Ahn and Shin, {Gu Choul} and Soree Park and Kang, {Hong Seok} and Rhee, {Jin Kyu} and Yang, {Sung Il} and Youhoon Chong and Kim, {Kyun Hwan}",
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Ahn, SH, Kim, DH, Lee, AR, Kim, BK, Park, YK, Park, ES, Ahn, S, Shin, GC, Park, S, Kang, HS, Rhee, JK, Yang, SI, Chong, Y & Kim, KH 2015, 'Substitution at rt269 in hepatitis B virus polymerase is a compensatory mutation associated with multi-drug resistance', PLoS One, vol. 10, no. 8, e0136728. https://doi.org/10.1371/journal.pone.0136728

Substitution at rt269 in hepatitis B virus polymerase is a compensatory mutation associated with multi-drug resistance. / Ahn, Sung Hyun; Kim, Doo Hyun; Lee, Ah Ram; Kim, Beom Kyung; Park, Yong Kwang; Park, Eun Sook; Ahn, SangHoon; Shin, Gu Choul; Park, Soree; Kang, Hong Seok; Rhee, Jin Kyu; Yang, Sung Il; Chong, Youhoon; Kim, Kyun Hwan.

In: PLoS One, Vol. 10, No. 8, e0136728, 31.08.2015.

Research output: Contribution to journalArticle

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T1 - Substitution at rt269 in hepatitis B virus polymerase is a compensatory mutation associated with multi-drug resistance

AU - Ahn, Sung Hyun

AU - Kim, Doo Hyun

AU - Lee, Ah Ram

AU - Kim, Beom Kyung

AU - Park, Yong Kwang

AU - Park, Eun Sook

AU - Ahn, SangHoon

AU - Shin, Gu Choul

AU - Park, Soree

AU - Kang, Hong Seok

AU - Rhee, Jin Kyu

AU - Yang, Sung Il

AU - Chong, Youhoon

AU - Kim, Kyun Hwan

PY - 2015/8/31

Y1 - 2015/8/31

N2 - 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 multidrug resistant HBV.

AB - 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 multidrug resistant HBV.

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