Novel hepatitis D-like agents in vertebrates and invertebrates

Abstract

Hepatitis delta virus (HDV) is the smallest known RNA virus and encodes a single protein. Until recently, HDV had only been identified in humans, where it is strongly associated with co-infection with hepatitis B virus (HBV). However, the recent discovery of HDV-like viruses in metagenomic samples from birds and snakes suggests that this virus has a far longer evolutionary history. Herein, using additional meta-transcriptomic data, we show that highly divergent HDV-like viruses are also present in fish, amphibians and invertebrates. Notably, the novel viruses identified here share HDV-like genomic features such as a small genome size of ~1.7kb in length, circular genomes, and self-complementary, unbranched rod-like structures. Coiled-coil domains, leucine zippers, conserved residues with essential biological functions and isoelectronic points similar to those in the human hepatitis delta virus antigens (HDAgs) were also identified in the putative non-human HDAgs. Notably, none of these novel HDV-like viruses were associated with hepadnavirus infection, supporting the idea that the HDV-HBV association may be specific to humans. Collectively, these data not only broaden our understanding of the diversity and host range of HDV in non-human species, but shed light on its origin and evolutionary history.

Snake deltavirus utilizes envelope proteins of different viruses to generate infectious particles

“…HDV infection affects around 20 million people worldwide 36 , however, it is currently somewhat of a neglected disease due to the fact that HBV vaccination is thought to also protect against HDV infection. The recent discovery of deltaviruses in the absence of hepadnaviral co-infection across a wide range of taxa 5, 6, 28 provided the first indications that deltaviruses could be much more enigmatic than originally thought. We found SDeV in several tissues of the infected snakes, indicating that the virus has a broad tissue tropism and further suggesting that SDeV does not rely on a hepadnavirus as its helper 6 .…”

“…The common ancestor of deltaviruses could be found among viroids of higher plants, since they show the highest similarities with HDV 4 . Since a deltavirus was already identified in termites 28 , one could hypothesize that the deltavirus ancestor was transmitted to Animalia from plants. Indeed, Bogaert and colleagues showed the presence of viroids in aphids feeding on infected plants 48 which could support the above hypothesis.…”

“…Deltaviruses are likely widespread both worldwide and across different taxa. So far novel deltaviruses have been found in snakes, birds, fish, amphibians, and invertebrates 5, 6, 28 . These findings add to the previously limited knowledge about the origin and evolution of HDV 7 .…”

“…Moreover, we could demonstrate the presence of both viral RNA and snake delta antigen (SDAg) in several tissues, indicating that the replication of SDeV is not restricted to the liver 6 , which likely holds true also for AvDV. To further support the idea that the evolutionary path of HDV is much longer than initially envisioned, more HDV-like agents were identified in fish, amphibians and invertebrates in early 2019 28 . Similar to AvDV and SDeV, the newly found deltaviruses were not associated with hepadnavirus infection 28 .…”

“…To further support the idea that the evolutionary path of HDV is much longer than initially envisioned, more HDV-like agents were identified in fish, amphibians and invertebrates in early 2019 28 . Similar to AvDV and SDeV, the newly found deltaviruses were not associated with hepadnavirus infection 28 . The new findings have raised the question if deltaviruses are indeed dependent on hepadnavirus co-infection.…”