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07.08.2020 | Original Article

Hepatitis B virus X gene mutants emerge during antiviral therapy and increase cccDNA levels to compensate for replication suppression

verfasst von: Chih-Lang Lin, Rong-Nan Chien, Yu-De Chu, Kung-Hao Liang, Ya-Hui Huang, Po-Yuan Ke, Kwang-Huei Lin, Yang-Hsiang Lin, Chau-Ting Yeh

Erschienen in: Hepatology International | Ausgabe 6/2020

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Abstract

Background

Hepatitis B virus (HBV) X gene (HBx) mutants can develop during the natural course of chronic HBV infection. However, little is known about whether the emergence of HBx mutants during long-term antiviral therapy is an adaptation of HBV to antiviral stress. This study was to identify HBx mutants that emerged in patients experiencing Lamivudine resistance or suboptimal treatment.

Methods

Forty-six Lamivudine-resistant patients and 46 patients with suboptimal treatment responses to Entecavir were enrolled in this study. HBx mutants were identified by sequence analysis and their roles in the HBV replication cycle were characterized.

Results

We show that deletion/truncation/insertion mutations were only detected in the Lamivudine resistance group, while synonymous mutations were found in both groups. Follow-up analyses revealed that five patients in the Lamivudine group developed hepatocellular carcinoma, while patients in the Entecavir group did not. These mutants were characterized by a significant decrease in transactivation of the pre-S1 promoter, and varying effects on transactivation of the X promoter. Co-transfection of HBx-mutant plasmid and HBV replication-competent clone into HepG2 cells resulted in increased nuclear-to-cytoplamic HBV core antigen, HBV-DNA ratios, and nuclear covalently closed circular DNA (cccDNA). Antiviral drug sensitivity assays revealed that these mutants exhibited a compensatory effect to counteract antiviral drug suppression, resulting in elevated secretory HBV-DNA levels.

Conclusions

Our study demonstrates that HBx mutants can emerge during Lamivudine or Entecavir therapy. These mutants exhibit altered transactivation of the HBV pre-S1 and X promoters, leading to increased cccDNA levels to compensate for replication suppression.

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Titel: Hepatitis B virus X gene mutants emerge during antiviral therapy and increase cccDNA levels to compensate for replication suppression
verfasst von: Chih-Lang Lin
Rong-Nan Chien
Yu-De Chu
Kung-Hao Liang
Ya-Hui Huang
Po-Yuan Ke
Kwang-Huei Lin
Yang-Hsiang Lin
Chau-Ting Yeh
Publikationsdatum: 07.08.2020
Verlag: Springer India
Erschienen in: Hepatology International / Ausgabe 6/2020
Print ISSN: 1936-0533
Elektronische ISSN: 1936-0541
DOI: https://doi.org/10.1007/s12072-020-10079-1

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Hepatitis B virus X gene mutants emerge during antiviral therapy and increase cccDNA levels to compensate for replication suppression