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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.
Juang et al. (Tue,) studied this question.