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Hepatitis delta virus (HDV) is a defective virus that requires hepatitis B virus (HBV) surface antigen for virion assembly and infection, and contains a negative single stranded circular RNA genome of 1.7 kilobases., HDV is classified into three geno-types (genotype I, II and III) based on genetic sequence analysis (Fig. 1). Genotype II shows approximately 75% homology to genotype I, and genotype III shares about 60 to 65% homol-ogy with genotype I and II. There are many variants within each genotype. Especially, HDV genotype II is further divided into two types (i.e., Ila and lib), with 77% nucleotide homology between the complete sequences of genotype Ila and lib. The nucleotide homology between genotype lib and Ilb-M, the newly identified lib variant, is 88–90%. Similarly, Ila variant was recently found in Siberia (Ila-Yakutia), which in comparison with Ila shows a similar degree of genetic differences. These genotypes show different geographical distributions and clinical pictures, which is thought to be caused by functional differences of genotype-specific sequences of HDV-RNA as well as HDAg protein.

The hepatitis delta virus (HDV) is a subviral agent that utilizes the envelope proteins of the hepatitis B virus (HBV) for cell to cell propagation. In infected human hepatocytes, the HDV RNA genome can replicate and associate with multiple copies of the delta protein to assemble a ribonucleoprotein (RNP). However the RNP cannot exit the cell because of the lack of an export system. This is provided by the HBV envelope proteins, which are capable of budding at an internal cellular membrane to assemble mature HDV virions when RNPs are present. This review covers advances in the molecular aspects of the HDV-HBV interactions, with an emphasis on the HBV properties that are instrumental in HDV maturation, in particular the central role of the small HBV envelope protein.

This review focuses on the RNAs of HDV, with emphasis on RNA structure, RNA transcription, and post-transcriptional RNA processing. Included is an evaluation of two current models of HDV RNA replication.

Hepatitis delta antigen (HDAg) was first detected in the nucleus of the hepatocytes of some patients infected with hepatitis B virus (HBV). The presence of HDAg was frequently associated with severe hepatitis. This antigen was initially thought to be a previously unrecognized HBV-encoded antigen, but later was found to be associated with a novel virus, hepatitis delta virus (HDV). HDAg is an internal component of the HDV virion particles, and, together with the viral RNA genome, forms viral nucleocapsid. There are ap-proximately 70 HDAg molecules per RNA molecule in each virion particle, but the precise structure of the nucleocapsid has not been determined. HDAg in virus preparations from most of the patients usually consists of two distinct forms of different size (27 and 24 kDa, termed the large and the small HDAg, L- and S-HDAg, respectively). The nucleocapsid is released from the virus particle after the latter is treated with nonionic detergents. Besides this struc-tural role, HDAg also plays a very critical role in the HDV life cycle by participating in various steps of viral replication, including viral RNA synthesis (by S-HDAg), virus assembly (by L-HDAg) and others. HDAg is the only known functional protein encoded by HDV RNA. It is encoded by the antigenomic-sense strand of HDV RNA, but is translated from a 0.8-kb mRNA, which is transcribed from the viral genomic RNA.

The genome of hepatitis delta virus (HDV) is the smallest known to infect man. Encoding just one protein, hepatitis delta antigen (HDAg), HDV relies heavily on host functions and on structural features of the viral RNA. A good example of this reliance is found in the process known as HDV RNA editing, which requires particular structural features in the HDV antigenome, and a host RNA editing enzyme, ADARl. During replication, the adenos-ine in the amber stop codon in the viral gene for the short form of HDAg (HDAg-S) is edited to inosine. As a result, the amber stop codon in the HDAg-S open reading frame is changed to a tryptophan codon; the reading frame is thus extended by 19 or 20 codons and the longer form of HDAg, HDAg-L, is produced. This change serves a critical purpose in the HDV replication cycle because HDAg-S supports viral RNA replication, while HDAg-L is required for virion packaging but inhibits viral RNA replication. This review will cover the mechanisms of RNA editing in the HDV replication cycle and the regulatory mechanisms by which HDV controls editing.

Replication and transcription of HDV proceed via RNA-dependent RNA synthesis. These reactions are thought to be catalyzed at least in part by host RNA polymerase II (RNAPII). Hepatitis delta antigen (HDAg), which is critical for these processes, was recently proposed to function as a transcription elongation factor for RNAPII. The involvement of a DNA-dependent RNA polymerase in RNA-dependent RNA synthesis is itself intriguing and poses fundamental questions as to how RNA synthesis initiates, elongates, and terminates on an unusual HDV RNA template. In addition, the presence of a ‘Viral’ transcription elongation factor is unprecedented in eukaryotes, whereas a few are known to exist in prokaryotes. Thus, the study of HDV replication and transcription should provide tremendous insight into the basic mechanism underlying RNAPII transcription.

In the early days following the discovery of the hepatitis delta virus (HDV) much emphasis was given on the severity of delta hepatitis and its rapid progression to cirrhosis and liver failure. However with time going on, evidence started to accumulate indicating that in several individuals, chronic HDV infection could run a benign course, with silent clinical and even biochemical features and that in such patients liver histology would be more consistent with the mild changes of chronic persistent hepatitis rather than with the severe necroinflammation and advanced fibrosis of chronic active hepatitis.- In particular the search for serological markers of HDV infection in the general population of several communities worldwide and among blood donors (Japan, Taiwan, Greece and Italy), revealed that the actual spectrum of delta hepatitis is very wide and heterogeneous and that similarly to the infection with the other known hepatitis viruses it can range from a very mild, clinically latent disease to florid active hepatitis and decompensated cirrhosis. With time going on and with the accumulation of new data from long-term follow-up studies, it also became obvious that the natural course of acute and chronic HDV infection is extremely variable and includes all pos-sibilities from complete cure and burning out to slow progression, rapid progression, develop-ment of cirrhosis and liver failure and development of hepatocellular carcinoma (HCC). Fur-thermore with the application of refined serological, virological and other laboratory techniques, the clinical aspects of HDV infection could be associated and linked meaningfully with nu-merous viral, host and other variables.

Hepatitis D virus (HDV) is a small defective virus with a single stranded circular RNA of 1.7 kb in size-. Its hepatitis B surface antigen (HBsAg) envelope is provided by the helper hepatitis B virus (HBV) for successfiil package and transmission of HDV,. The antigenomic strand of HDV encodes a single protein, hepatitis delta antigen (HDAg) of two molecular weight forms. The large form HDAg with a 19-amino acid extension at the C-terminus plays a key role in the package of HDV and suppresses viral replication in a trans-dominant negative manner, while the small form plays an essential role in trans-activating the replication of HDV RNA.,