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Hepatitis D virus (HDV), discovered 40 years ago, is a unique virus requiring hepatitis B virus (HBV) for replication. HDV, with a 1.7 kb circular single-stranded RNA genome, uses HBV surface proteins for its envelope. Its replication involves the delta antigen (HDAg), which interacts with cellular RNA polymerase. HDAg exists in two forms (small and large) with differing functions: S-HDAg promotes replication, while L-HDAg may inhibit S-HDAg and is crucial for assembly. HDV's origin is unknown, but its RNA shares properties with plant viroids and cellular ribozymes. The discovery of a cellular protein, DIPA, with sequence similarity to HDAg suggests a possible cellular origin for HDV, potentially through the capture of a DIPA gene.

Hepatitis D virus (HDV) was discovered 40 years ago in the liver of individuals chronically infected with hepatitis B virus (HBV) [1], a liver-specific pathogen present in ca. 250 million people. HDV is classified as the prototype and unique member of the Deltavirus genus. HDV forms enveloped particles with an average diameter of 36 nm that consists of cell-derived lipid vesicles harboring HBV surface proteins coating an inner ribonucleoprotein (RNP) [1]. This RNP is composed of a multimer of the HDV-encoded delta antigen (HDAg) [2] that is associated with one copy of a 1.7 kb long circular single strand HDV RNA exhibiting self-annealing properties [2]. Although HDAg was initially considered as a novel HBV antigen [3], it was later shown to be associated with a small RNA as a transmissible and defective agent that uses the HBV envelope glycoproteins (GP) for its propagation, hence reflecting its nature of obligate satellite of HBV [4]. For cell egress of its RNPs, HDV relies on the assistance of the helper HBV for the provision of GPs and a budding mechanism. Their envelopment subsequently allows targeting and entry of HDV particles to human hepatocytes via mechanisms that depend on the same host factors that govern the early entry events of HBV itself. Although HBV-related viruses (i.e., hepadnaviruses) are found in a number of mammals, HDV has thus far only been found in humans [1].

2. Current Hypotheses of HDV Origin

It is noteworthy that the origin of HDV is currently unknown. The HDV genome is unique and the smallest among animal viruses but shares some properties with some plant agents called viroids [5]. Indeed, the replication of HDV RNA involves the HDAg-mediated subversion of cellular RNA polymerase(s) (RNAP), such as Pol-II [6]. Both genomic HDV RNA and antigenomic RNA (its replication intermediate) strands include ribozyme autocatalytic, self-cleaving elements. However, most known viroids (i.e., pospiviroids) replicate by an asymmetrical rolling-circle mechanism. This pathway involves the generation of linear multimeric head-to-tail RNAs of negative polarity from circular RNAs of positive polarity by host RNAP(s). Interestingly, cells from highly divergent organisms express several HDV-like cellular ribozymes [7], which raises the possibility that HDV RNA originated from the cell transcriptome itself, in agreement with the finding that circular RNA (circRNA) species are abundant in cells [8]. The antigenomic RNA encodes for two forms of proteins based on RNA editing [9] and are referred to as small (S-HDAg, 195 amino acids) and large (L-HDAg, 214 amino acids) delta antigen [10]. S-HDAg promotes replication [11], whereas L-HDAg has been claimed to act as a dominant inhibitor of S-HDAg [12,13] and plays an essential role in virus assembly [14].

A cellular protein termed delta-interacting protein A (DIPA), initially identified as an HDAg ligand in a yeast two-hybrid screen [15], was proposed to represent a cellular ancestor of HDAg. DIPA and HDAg have shown 24% of protein sequence identity and 54% of similarity. Both proteins form oligomers through the coiled-coil domain, and it was suggested that the DIPA gene is a homolog of HDV and that capture of DIPA transcr