Hepatitis D virus is a unique human pathogen. With a circular, negative stranded RNA genome of ~1700 nucleotides, it is the smallest known human virus. Formation of the HDV particle depends on co-infection of cells with a helper virus, hepatitis B virus. Once thought to be specific for humans, related viruses have now been identified in birds and snakes – in the absence of hepatitis B virus.
The HDV genome is 70% base paired and folds upon itself in a tight rod-like structure (pictured). The RNA molecule, replicated by cellular RNA polymerase II, encodes two proteins, small and large delta antigens, from a single open reading frame. Small delta antigen is required for RNA replication, and large delta antigen participates in virus assembly. The HDV particle comprises the nucleocapsid packaged within an envelope that contains the surface protein of the helper, hepatitis B virus.
Avian HDV-like virus was discovered during a study of the RNA transcriptome of healthy water birds. The circular RNA genome of 1,706 bases encodes a delta antigen with 32% amino acid similarity to human HDV delta antigen. The viral RNA is folded into a rodlike structure, and contains sequences resembling the self-cleaving ribozyme of HDV. In the HDV genome, editing of a UAG stop codon to UGG encoding tryptophan extends the reading frame by 18 amino acids. This post-transcriptional modification leads to the synthesis of large delta antigen, which contains a isoprenylation site required for particle assembly. The avian open reading frame does not encode the UAG stop codon, but a +1 frameshift could extend the protein by 18 amino acids. However this putative large avian delta antigen does not contain an isoprenylation site.
Snake HDV was identified in several sick boa constrictors and a water python from the same colony. Sequence analysis of RNA from brain, blood, and liver revealed the presence of a circular RNA genome of 1,711 nucleotides. The viral RNA can be folded into a rodlike structure and ribozyme sequences are present. The single open reading frame encodes a small delta antigen with 55% and 37% amino acid identity with human and avian delta antigens, respectively. Editing of a UAG stop codon would extend snake small delta antigen by 22 amino acids. RT-PCR confirmed presence of viral RNA in liver tissue of the original snakes and in 3 of 20 blood samples obtained from a different snake breeder. Both small and large delta antigens were detected by western blot analysis of liver tissue. Immunohistochemical analysis revealed viral antigen in brain, liver, lung, kidney and spleen. These observations indicate that snake HDV is replicating in multiple tissues.
No hepatitis B-like virus was detected in any of the birds or snakes examined in the two studies. The authors suggest that an unidentified enveloped virus might serve as a helper virus, allowing packaging of the avian and snake delta viruses. The observation that co-housed snakes of different species were infected with sHDV suggests horizontal transmission via virus particles.
The finding of HDV-like viruses in other animals challenges the idea that HDV arose in humans. It seems likely that all three deltaviruses share a common ancestor that arose before humans. This ancestor might not have formed virus particles, but simply existed as replicons that multiplied in cells and spread during mitosis. At some point these cells might have been infected with another virus which enabled the delta replicons to form particles and spread extracellularly.
I wonder if avian HDV-like and snake HDV are the correct names for these viruses, as there is no evidence that they are associated with hepatitis. A future name change may be indicated.