Distinct dual antiviral mechanism that enhances hepatitis B virus mutagenesis and reduces viral DNA synthesis

Yumeng Z. McDaniel, Steven Patterson, Louis M Mansky

Research output: Contribution to journalArticle

Abstract

Reverse transcriptase (RT) is an essential enzyme for the replication of retroviruses and hepadnaviruses. Current therapies do not eliminate the intracellular viral replication intermediate termed covalently closed circular (ccc) DNA, which has enhanced interest in hepatitis B virus (HBV) reverse transcription and cccDNA formation. The HBV cccDNA is generated as a plasmid-like episome in the host cell nucleus from the protein-linked relaxed circular (rc) DNA genome in incoming virions during HBV replication. The creation of the cccDNA via conversion from rcDNA remains not fully understood. Here, we sought to investigate whether viral mutagens can effect HBV replication. In particular, we investigated whether nucleoside analogs that act as viral mutagens with retroviruses could impact hepadnaviral DNA synthesis. We observed that a viral mutagen (e.g., 5-aza-2′-deoxycytidine, 5-aza-dC or 5-azacytidine, 5-aza-C) severely diminished the ability of a HBV vector to express a reporter gene following virus transfer and infection of target cells. As predicted, the treatment of 5-aza-dC or 5-aza-C elevated the HBV rcDNA mutation frequency, primarily by increasing the frequency of G-to-C transversion mutations. A reduction in rcDNA synthesis was also observed. Intriguingly, the cccDNA nick/gap region transcription was diminished by 5-aza-dC, but did not enhance viral mutagenesis. Taken together, our results demonstrate that viral mutagens can impact HBV reverse transcription, and propose a model in which viral mutagens can induce mutagenesis during rcDNA formation and diminish viral DNA synthesis during both rcDNA formation and the conversion of rcDNA to cccDNA.

Original languageEnglish (US)
Article number104540
JournalAntiviral Research
Volume170
DOIs
StatePublished - Oct 1 2019

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Viral DNA
Hepatitis B virus
Mutagenesis
Antiviral Agents
Mutagens
decitabine
Azacitidine
Circular DNA
Retroviridae
Virus Replication
Reverse Transcription
Plasmids
Hepadnaviridae
RNA-Directed DNA Polymerase
Virus Diseases
Mutation Rate
Cell Nucleus
Reporter Genes
Nucleosides
Virion

Keywords

  • Hepadnavirus
  • Lethal mutagenesis
  • Polymerase
  • Reverse transcription

PubMed: MeSH publication types

  • Journal Article

Cite this

Distinct dual antiviral mechanism that enhances hepatitis B virus mutagenesis and reduces viral DNA synthesis. / McDaniel, Yumeng Z.; Patterson, Steven; Mansky, Louis M.

In: Antiviral Research, Vol. 170, 104540, 01.10.2019.

Research output: Contribution to journalArticle

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