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Usurping Host DNA Repair Mechanisms Enables Hepatitis B Virus to Evade Replication Inhibitors

By BiotechDaily 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).
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




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