Usurping Host DNA Repair Mechanisms Enables Hepatitis B Virus to Evade Replication Inhibitors
By LabMedica International staff writers Posted on 08 Jul 2013 |
Image: The interaction of HBV circular DNA with host UNG (uracil-DNA glycosylase), (Photo courtesy of Kanazawa University).
A team of Japanese virologists used a duck hepatitis B virus (DHBV) model to examine the molecular pathways involved in maintaining the integrity of the virus' circular DNA (covalently closed circular DNA or cccDNA), which modulates the transition from an acute infection into a chronic disease.
The study focused on a group of enzymes called apolipoprotein B mRNA editing catalytic polypeptide (APOBEC) proteins. This family of proteins has been suggested to play an important role in innate antiviral immunity. Recently, antiviral cytidine deaminase APOBEC proteins were shown to generate uracil residues in the viral cytoplasmic nucleocapsid (NC) DNA (partially double-stranded DNA) through deamination, resulting in cytidine-to-uracil (C-to-U) hypermutation of the viral genome, which blocked viral replication. Of particular interest was the role of APOBEC3G, which had been found to interfere with HIV replication.
As uracil residues in human genomic DNA are removed by the enzyme uracil-DNA glycosylase (UNG), resulting in the creation of abasic sites that are repaired by downstream repair factors, investigators at the Kanazawa University Graduate School of Medical Science (Japan) used an avian counterpart for HBV—duck HBV (DHBV)—to investigate the affect of host UNG on viral hypermutation in cccDNA.
Results published in the May 16, 2013, online edition of the journal PLOS Pathogens revealed that the hepatitis virus was able to subvert host UNG to repair the hypermutation introduced by APOBEC3G. When UNG activity was inhibited, APOBEC3G-induced hypermutation of cccDNA was enhanced.
The investigators measured the replication ability of purified cccDNA and found that recloned cccDNA from cells expressed by both APOBEC3G and UNG inhibitor protein replicated less efficiently due to higher hypermutation rates.
Transfection experiments showed that cccDNA hypermutation was enhanced by UNG inhibition in APOBEC3G expressing cells, resulting in a significant decrease in viral production. The investigators wrote that, “We speculate that the balance between APOBECs and UNG activities on mutation frequency decides the consequence to hepadnaviruses [the viral family that includes hepatitis B]: deleterious mutations vs. diversification.”
Future research will investigate the possible role of APOBECs and host factors such as UNG in the emergence of drug-resistant strains of HBV.
Related Links:
Kanazawa University Graduate School of Medical Science
The study focused on a group of enzymes called apolipoprotein B mRNA editing catalytic polypeptide (APOBEC) proteins. This family of proteins has been suggested to play an important role in innate antiviral immunity. Recently, antiviral cytidine deaminase APOBEC proteins were shown to generate uracil residues in the viral cytoplasmic nucleocapsid (NC) DNA (partially double-stranded DNA) through deamination, resulting in cytidine-to-uracil (C-to-U) hypermutation of the viral genome, which blocked viral replication. Of particular interest was the role of APOBEC3G, which had been found to interfere with HIV replication.
As uracil residues in human genomic DNA are removed by the enzyme uracil-DNA glycosylase (UNG), resulting in the creation of abasic sites that are repaired by downstream repair factors, investigators at the Kanazawa University Graduate School of Medical Science (Japan) used an avian counterpart for HBV—duck HBV (DHBV)—to investigate the affect of host UNG on viral hypermutation in cccDNA.
Results published in the May 16, 2013, online edition of the journal PLOS Pathogens revealed that the hepatitis virus was able to subvert host UNG to repair the hypermutation introduced by APOBEC3G. When UNG activity was inhibited, APOBEC3G-induced hypermutation of cccDNA was enhanced.
The investigators measured the replication ability of purified cccDNA and found that recloned cccDNA from cells expressed by both APOBEC3G and UNG inhibitor protein replicated less efficiently due to higher hypermutation rates.
Transfection experiments showed that cccDNA hypermutation was enhanced by UNG inhibition in APOBEC3G expressing cells, resulting in a significant decrease in viral production. The investigators wrote that, “We speculate that the balance between APOBECs and UNG activities on mutation frequency decides the consequence to hepadnaviruses [the viral family that includes hepatitis B]: deleterious mutations vs. diversification.”
Future research will investigate the possible role of APOBECs and host factors such as UNG in the emergence of drug-resistant strains of HBV.
Related Links:
Kanazawa University Graduate School of Medical Science
Latest BioResearch News
- Genome Analysis Predicts Likelihood of Neurodisability in Oxygen-Deprived Newborns
- Gene Panel Predicts Disease Progession for Patients with B-cell Lymphoma
- New Method Simplifies Preparation of Tumor Genomic DNA Libraries
- New Tool Developed for Diagnosis of Chronic HBV Infection
- Panel of Genetic Loci Accurately Predicts Risk of Developing Gout
- Disrupted TGFB Signaling Linked to Increased Cancer-Related Bacteria
- Gene Fusion Protein Proposed as Prostate Cancer Biomarker
- NIV Test to Diagnose and Monitor Vascular Complications in Diabetes
- Semen Exosome MicroRNA Proves Biomarker for Prostate Cancer
- Genetic Loci Link Plasma Lipid Levels to CVD Risk
- Newly Identified Gene Network Aids in Early Diagnosis of Autism Spectrum Disorder
- Link Confirmed between Living in Poverty and Developing Diseases
- Genomic Study Identifies Kidney Disease Loci in Type I Diabetes Patients
- Liquid Biopsy More Effective for Analyzing Tumor Drug Resistance Mutations
- New Liquid Biopsy Assay Reveals Host-Pathogen Interactions
- Method Developed for Enriching Trophoblast Population in Samples