Hepatitis D Virus Infection
Tarik Asselah and Mario Rizzetto
Hepatitis D virus (HDV), also known as hepatitis delta virus, is a defective, hepatotropic pathogenic agent. The life cycle of HDV requires the hepatitis B surface antigen (HBsAg) provided by hepatitis B virus (HBV).1 Like HBV, HDV is transmitted by the parenteral route through infectious body fluids; intravenous drug users are at highest risk for infection because of contaminated syringes.2,3 Key features of the infection are its unique biologic characteristics and ominous medical effect. Clinical studies have shown that chronic hepatitis D is the most severe and progressive form of viral hepatitis in humans.2 The infection is ubiquitous, yet 40 years after it was identified, the prevalence remains undetermined in many parts of the world. In three recent meta-analyses, the number of HDV-infected persons worldwide ranged from 12 million to 72 million, underscoring the heterogeneity of current epidemiologic data.3 Valid therapies to cure hepatitis D are an urgent need, and new therapeutic strategies are in development.
A Unique Human Pathogen
HDV, the smallest viral pathogen infecting humans, has biologic features similar to those of the viroids of plants.4 It belongs to the genus deltavirus within the family of Kolmioviridae.5 Eight genotypes with 81 to 89% sequence homology and many subgenotypes have been identified.6 Genotype 1, the most widely distributed, predominates in Europe and North America. Genotype 3, present only in the Amazon basin, has been associated with outbreaks of fulminant hepatitis D,3 whereas genotype 5, present in Africa, is associated with a more benign disease and has a better response to interferon than does the ubiquitous genotype 1.7
The genome is a circular, single-stranded RNA of approximately 1700 nucleotides. It is too small to code for replicative enzymes or envelope proteins and codes only for a small, nonenzymatic protein, hepatitis delta antigen (HDAg).8 Three HDV RNA species are found in humans: a 1.7-kb genomic RNA in the virions, a complementary antigenomic RNA of positive polarity and the same size in the liver, and a 0.8-kb messenger RNA (mRNA) of antigenomic polarity in the liver; the mRNA contains an open reading frame for translation of HDAg. The genomic and antigenomic RNAs contain a domain of approximately 100 nucleotides that acts as a ribozyme, cleaving the viral RNA at specific sites without the participation of viral encoded enzymes.9 Although in natural infections, intrahepatic HDV RNA replicates without assistance from HBV, HDV relies on HBV for all other functions of its life cycle, including viral packaging, infectivity, transmission, and inhibition of host immunity.2,8-12