Mechanisms of Ribozyviria Transmission in Animal and Vegetal Holobionts

Dear Colleagues,

Eukaryotes form composite multicellular organisms called “holobionts” that live in symbiosis with their microbiomes, including viruses. The vast majority of RNA viruses live in Eukaryotes [1], including the smallest subviral forms of viroids and viroid-like covalently closed circular (ccc) RNAs that hijack cellular enzymes for replication [2]. Hepatitis Delta Virus (HDV) is the progenitor of a conspicuous group of viroid-like, negative-sense single-stranded RNA viruses forming the new viral realm of Ribozyviria [3–6]. These viruses behave as satellite ribonucleic acids that may encode non-structural proteins and are encapsidated within the coat proteins of helper symbiont viruses [7–10]. Ribozyviria share at least two of the following characteristics: presence of enveloped spherical virions; presence of a circular negative-sense RNA genome containing ribozymes and encoding an HDAg homolog; and need for an unrelated helper virus for the assembly of infectious virions [7–10]. So far, the phylogenetic tree of Delta Antigen (HDAg) homologs has been found to include eleven genera forming monophyletic clades. Since the original characterization of chimeric HDV virion in humans, it has become evident that the envelope Hepatitis B surface Antigen (HBsAg) provided by Hepatitis B Virus has a specific composition of the HBsAg constitutive proteins (ratio of pre-S1, pre-S2, and S antigens) [11,12]. Following this, it has been found that defective HBsAg particles behaving as extracellular vesicles export and circulate hepatic mRNAs [13,14] and, interestingly, that miRNA signatures carried by circulating HBsAg particles are comparable in patients with active HBV or HDV infection and disease, but significantly different from HBsAg carriers with inactive HBV infection (i.e., without chronic hepatitis B and/or D) [15,16]. HDV could be consistently detected sporadically, even in the absence of HBV infection, but without any evidence of efficient persistence and spread of HDV infection without the mandatory support of a specific expression of HBsAg [17–19]. Finally, current anti-HDV therapy relies on the specific blockage of HBV and HDV entry into the hepatocyte in vitro and in vivo by means of a 47-aa synthetic N-acetilated HBV-pre-S1-derived lipopeptide (Myrcludex B, Bulevirtide) that binds the sodium taurocholate co-transporting polypeptide (NTCP) [20].

All of this evidence poses the tantalizing question of which specific features are required for efficient extracellular export of the HDV-RNA genome as well as other intranuclear RNA forms and Ribozyviria. This Special Issue of Viruses is dedicated to understanding the mechanisms of transmission of Ribozyviria in and between vegetal and animal holobionts, addressing this interdisciplinary issue with a system medicine approach to foster the cross-fertilization of ideas between scientists and researchers of different disciplines.

References

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Prof. Dr. Maurizia Rossana Brunetto
Prof. Dr. Ferruccio Bonino
Guest Editors

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• viroid-like RNAs
• holobionts
• RNA viruses
• circular RNA genomes
• satellite viruses
• HBsAg (hepatitis b surface antigen)