Investigating the Genetic Diversity of Hepatitis Delta Virus in Hepatocellular Carcinoma (HCC): Impact on Viral Evolution and Oncogenesis in HCC

Horng Heng Juang, Chao Wei Hsu, Kang Shuo Chang, Shan Bei Iang, Yang Hsiang Lin, Mei Chao*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

2 Scopus citations

Abstract

Hepatitis delta virus (HDV), an RNA virus with two forms of the delta antigen (HDAg), relies on hepatitis B virus (HBV) for envelope proteins essential for hepatocyte entry. Hepatocellular carcinoma (HCC) ranks third in global cancer deaths, yet HDV’s involvement remains uncertain. Among 300 HBV-associated HCC serum samples from Taiwan’s National Health Research Institutes, 2.7% (8/300) tested anti-HDV positive, with 62.7% (5/8) of these also HDV RNA positive. Genotyping revealed HDV-2 in one sample, HDV-4 in two, and two samples showed mixed HDV-2/HDV-4 infection with RNA recombination. A mixed-genotype infection revealed novel mutations at the polyadenylation signal, coinciding with the ochre termination codon for the L-HDAg. To delve deeper into the possible oncogenic properties of HDV-2, the predominant genotype in Taiwan, which was previously thought to be less associated with severe disease outcomes, an HDV-2 cDNA clone was isolated from HCC for study. It demonstrated a replication level reaching up to 74% of that observed for a widely used HDV-1 strain in transfected cultured cells. Surprisingly, both forms of HDV-2 HDAg promoted cell migration and invasion, affecting the rearrangement of actin cytoskeleton and the expression of epithelial–mesenchymal transition markers. In summary, this study underscores the prevalence of HDV-2, HDV-4, and their mixed infections in HCC, highlighting the genetic diversity in HCC as well as the potential role of both forms of the HDAg in HCC oncogenesis.

Original languageEnglish
Article number817
JournalViruses
Volume16
Issue number6
DOIs
StatePublished - 21 05 2024

Bibliographical note

Publisher Copyright:
© 2024 by the authors.

Keywords

  • cell migration and invasion
  • delta antigen
  • hepatitis delta virus
  • hepatocellular carcinoma
  • RNA recombination
  • Liver Neoplasms/virology
  • Humans
  • Middle Aged
  • RNA, Viral/genetics
  • Genotype
  • Male
  • Phylogeny
  • Genetic Variation
  • Hepatitis Delta Virus/genetics
  • Hepatitis D/virology
  • Carcinoma, Hepatocellular/virology
  • Virus Replication
  • Taiwan
  • Female
  • Aged
  • Hepatitis B virus/genetics
  • Carcinogenesis/genetics
  • Evolution, Molecular

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