As discovered in 1986, the HDV viral particle contains a covalently closed circular single-stranded RNA genome consisting of 1678 nucleotides with negative polarity. This genome is currently the smallest known genome of an animal virus. Interestingly, its properties are more similar to the subviral particles of the plant kingdom known as viroids. Much like viroids, the HDV genome is folded into a rod-like secondary structure that is dependent on the RNA polymerase of the host cell enabling a double-rolling circle replication pathway (Figure 1). However, unlike viroids, a complementary subgenomic mRNA encodes a single protein, the HDAg, the 24 kDa small delta antigen (195 amino acids, SHDAg), whilst an edited form of this mRNA encodes the 27 kDa, 214 amino acids long, large delta antigen (LHDAg).[21,22] Each protein appears to have its own unique role. SHDAg promotes replication of the genomic RNA whilst LHDAg participates in the HDV RNA enveloping process. The two proteins are essentially identical except for a major difference in the prenylated C terminus where the additional 19 amino acids are found. This prenylation appears to be a necessity for future interaction with the HBV envelope proteins. Once assembled, the small and large antigen bind with the rod-like circular RNA creating together the HDV ribonucleoprotein (RNP) complex. The now formed RNP complex completes the cycle by interacting with the HBV envelope proteins to form the HDV viral particle. The HBV envelope proteins consist of 3 HBV surface antigen (HBsAg) isoforms, small (S), medium (M) and large (L). Utilizing the HBV envelope, the HDV particle penetrates the hepatocyte cell membrane in the same way the HBV virion makes its entry (Figure 2). Entry is facilitated via interaction of the pre-S1 domain of the L protein with the bile acid transporter sodium taurocholate co-transporting polypeptide (NTCP). This process requires prior N-terminal modification of the L protein by myristic acid, a process termed myristoylation. Following myristoylation, the previously interior viral domain is translocated to the virion surface and becomes available for NTCP binding. Once inside the hepatocyte cytoplasm, the RNP is navigated via the HDAg nuclear localization signal into the nucleus where the replication cycle begins anew.
The HDV virion. The viral particle contains a covalently closed circular single-stranded RNA genome. The HDV genome is folded into a rod-like secondary structure along with the small and large delta antigen. The virion envelope contains the small, medium and large HBV surface antigen
Hepatitis D virus life cycle and entry into the hepatocyte. Entry into the hepatocyte is obtained by interaction of the HBsAg L protein with the NTCP receptor. Once inside the hepatocyte cytoplasm, the HDV ribonucleoprotein is navigated via the HDAg nuclear localization signal into the nucleus where the replication cycle begins. Therapeutic agents and their effect inside the hepatocyte are marked (full immunologic and hepatocyte mechanism of action for PEG-interferon lambda not shown in figure)
Not surprisingly, the formed 36-nm viral particle is the smallest known human RNA virus. The lack of an efficient proofreading ability by the virus has resulted in the identification of 8 HDV genotypes so far. However, studies have shown that some viral sequences appear highly conserved across genotypes focussing attention to viral constraints regarding the adequate function and structure of its only protein.
J Viral Hepat. 2022;29(4):240-251. © 2022 Blackwell Publishing