HDV-Like Viruses

Abstract

Hepatitis delta virus (HDV) is a defective human virus that lacks the ability to produce its own envelope proteins and is thus dependent on the presence of a helper virus, which provides its surface proteins to produce infectious particles. Hepatitis B virus (HBV) was so far thought to be the only helper virus described to be associated with HDV. However, recent studies showed that divergent HDV-like viruses could be detected in fishes, birds, amphibians, and invertebrates, without evidence of any HBV-like agent supporting infection. Another recent study demonstrated that HDV can be transmitted and propagated in experimental infections ex vivo and in vivo by different enveloped viruses unrelated to HBV, including hepatitis C virus (HCV) and flaviviruses such as Dengue and West Nile virus. All this new evidence, in addition to the identification of novel virus species within a large range of hosts in absence of HBV, suggests that deltaviruses may take advantage of a large spectrum of helper viruses and raises questions about HDV origins and evolution.

Keywords: HDV-like viruses; evolution; helper virus; origin.

Figure 1

Bayesian phylogenetic tree of mammalian deltaviruses and HDV-like viruses. Small delta antigen (DAg) nucleotide sequences from published mammalian and invertebrate deltaviruses, including representative HDV clades, were aligned using the translated protein option (without the trust insertion -F) implemented in PRANK [37,38]. Phylogenetic reconstruction of DAg was carried out using the resulting protein alignment and the best amino acid substitution model (LG+F+G) inferred by Smart Model Selection [39]. The Bayesian analysis was carried out with MrBayes, using 2,000,000 generations with a tree sampling every 1000 generations and a burn-in of 500 trees. The final tree was rooted with the termite HDV-like virus. Tree edition was performed with iTOL [40].

Figure 2

Schematic representation of RNA editing during deltaviruses replication (A) and putative L-DAgs generated via ADAR1 (B). The incoming viral genome, a circular ssRNA molecule of negative polarity (genomic RNA), serves as a template for the synthesis of DAg encoding mRNAs and circular RNAs of antigenomic polarity. The mRNA produced at the early stages of deltaviruses replication contains an amber stop codon (UAG) and produces the small form of DAgs. In a fraction of the antigenomic RNAs, the adenosine in the amber stop codon is deaminated to inosine (UIG) by the host RNA editing enzyme ADAR1. The edited mRNAs contain a tryptophan (W) codon instead of the amber stop codon and additional codons are translated to yield the large form of DAgs. The asterisk depicts the presence of a CXXQ motif in the C-terminus of L-HDAg required for isoprenylation.