Hepatitis B virus X gene mutants emerge during antiviral therapy and increase cccDNA levels to compensate for replication suppression.
Antiviral Agents
/ pharmacology
DNA, Circular
/ genetics
DNA, Viral
/ genetics
Drug Resistance, Viral
Hepatitis B virus
/ genetics
Hepatitis B, Chronic
/ drug therapy
Humans
Lamivudine
/ pharmacology
Liver Neoplasms
/ drug therapy
Mutation
Trans-Activators
Viral Regulatory and Accessory Proteins
Virus Replication
Entecavir
Lamivudine
Pre-S1 promoter
Suboptimal response
Transactivation
Journal
Hepatology international
ISSN: 1936-0541
Titre abrégé: Hepatol Int
Pays: United States
ID NLM: 101304009
Informations de publication
Date de publication:
Dec 2020
Dec 2020
Historique:
received:
19
05
2020
accepted:
22
07
2020
pubmed:
10
8
2020
medline:
30
10
2021
entrez:
10
8
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 32770306
doi: 10.1007/s12072-020-10079-1
pii: 10.1007/s12072-020-10079-1
doi:
Substances chimiques
Antiviral Agents
0
DNA, Circular
0
DNA, Viral
0
Trans-Activators
0
Viral Regulatory and Accessory Proteins
0
hepatitis B virus X protein
0
Lamivudine
2T8Q726O95
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
973-984Subventions
Organisme : Chang Gung Memorial Hospital
ID : CMRPG2B0463
Organisme : Chang Gung Memorial Hospital
ID : CRRPG2H0081
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