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Hepatitis A virus (HAV) Type species of the genus Hepatovirus. Virion diameter 27-29nm, density in CsC1: 1.32-1.34 g/ml, sedimenting at 160S in sucrose. The genome RNA is positive-sense, 7.48kb in length, with a VPg protein covalently attached at the 5' end, and poly A at the 3' end. There is a single open reading frame encoding a polyprotein of 2235 amino acids. The virus replicates in various primate cell cultures after adaptation, usually without cyto-pathic effects. Causes enterically transmitted 'short incubation' hepatitis (less than 6 weeks) in humans. The virus is present in the feces during the prodromal phase of the disease but usually disappears about the time jaundice appears. Chronic carriers of the virus are not seen and the virus does not cause progressive liver disease. Epidemics of hepatitis A are usually due to water- or food-borne infection. Antibodies may be demonstrated by CFT, immune adherence, hemagglutination and radioimmunoassay. They appear soon after the onset of jaundice and persist. They increase in frequency with age and reach a peak at age 50 years. Chimpanzees, owl monkeys and marmosets are susceptible to experimental infection and the virus can be demonstrated in their hepatocytes.

Simian virus strains related to but genetically distinct from the human virus have been isolated from African green and cynomolgus monkeys. An excellent formalin-inactivated vaccine is now licensed for use in people at risk for hepatitis A infection.

Synonyms: catarrhal jaundice virus; epidemic jaundice virus of humans.

Lemon SM (1992) Rev Med Virol 2, 73 Ross BC et al (1991) Adv Virus Res 39, 209 Werzberger A et al (1992) New Engl J Med 327, 453

Hepatitis B virus (HBV) Type species of the genus Orthohepadnavirus. Causes 'long incubation' hepatitis (more than 60 days). Classically, infection results from the inoculation of serum from a carrier during blood transfusion, vaccination, tattooing or ear-piercing with inadequately sterilized instruments. However, non-parenteral routes are also important and many cases result from domestic and sexual contact, especially homosexual practices. The complete virus is an enveloped particle 42nm in diameter, but small spherical particles 22nm in diameter and tubular forms of the same diameter but up to 100nm long, are also present in the plasma of carriers. The viral genome is 3.2kb long, and serves in infected cells as the template for a 3.4kb RNA species (pre-genomic RNA), with redundant ends and short sequence repetitions, that is packaged into core particles. The pre-genomic RNA is then reverse-transcribed to form negativestrand DNA, which in turn serves as a template for positive-strand DNA synthesis. Virus may be detected in the plasma by electron microscopy or by various tests for one of three viral antigens: (1) surface antigen (HBsAg), present on the surface of all three types of virus particle; (2) core antigen (HBcAg), which is exposed when the outer membrane of the complete virus is disrupted with a detergent; and (3) e antigen (HBeAg), present in the core of the complete particles. Presence of e antigen in serum suggests high infectivity. HBsAg is present in the blood 4 weeks prior to the development of symptoms and usually disappears 6 weeks after the onset of symptoms. If present beyond 13 weeks it is likely that the patient will become a chronic carrier and may develop chronic liver disease. Anti-HBs does not usually appear until convalescence. HBcAg does not appear in the blood. Anti-HBc appears during the disease and, unlike anti-HBs, persists for years and is a valuable marker of previous infection. HBeAg appears during the incubation period but disappears more rapidly than HBsAg. Persistence beyond 3-4 weeks may herald a chronic infection, which carries risk of hepatic cirrhosis or hepatocellular carcinoma. Not all chronic carriers of Hepatitis B virus develop chronic liver disease. A few infections result in acute hepatic failure probably due to an antigen-antibody reaction. Immune serum globulin (ISG) and hyperimmune globulin (HIG) are effective in providing passive immunity. A plasma-derived vaccine consisting of HBsAg is effective and widely used, especially in developing countries. This has been replaced in most other countries by genetically engineered vaccines derived from HBsAg produced in yeast (Recombivax, Engerovax), which provide solid immunity after three injections. A variety of non-human primates can be infected and on several occasions zoo primates, especially chimpanzees, have been found to be chronic carriers. The source of their infection is not clear but may be in the wild since some human cases have been associated with contact with wild, nonhuman primates, and hepadnaviruses have now been found in several species including chimpanzees, gibbons, orangutans and woolly monkeys. Synonym: serum hepatitis virus.

Ganem D and Varmus HE (1987) Annu Rev Biochem 56, 651

Hu X et al (2000) Proc Natl Acad Sci 97, 1661 MacDonald DM et al (2000) J Virol 74, 4253 Margolis HS et al (1991) Semin Liver Dis 11, 84 Takahashi K et al (2000) Virology 267, 58 Warren KS et al (1999) J Virol 73, 7860

'Hepatitis C-like viruses' Originally a genus in the family Flaviviridae which includes Hepatitis C and related viruses. In 1996 it was changed to Hepacivirus.

Hepatitis C virus (HCV) The only species in the genus Hepacivirus and the major cause of hepatitis non-A non-B. The virion has not been visualized but it is believed, from physicochemical studies of the infectious agent, to be spherical, enveloped and about 50nm in diameter. In 1988 the genome of Hepatitis C was molecularly cloned from infected chimpanzee tissues, and later completely sequenced. It is a linear, single-stranded RNA of positive polarity with a 5' untranslated region of about 340 nucleotides followed by a large open reading frame of about 9400 nucleotides and a short 3' untranslated region of 50 nucleotides, with no 3'-terminal poly A. The genome organization is similar to that of flaviviruses and pestiviruses, and encodes a large protein (3000 amino acids) that is cleaved into seven proteins: three structural and four non-structural. The gene order is 5'-C-E1-E2-p7-NS2-NS3-NS4A,NS4B-NS5A-NS5B-3'. The C (core) protein is highly basic and not gly-cosylated. E1 and E2 are glycosylated membrane proteins. In vitro replication has not so far been observed, so little is known concerning the non-structural proteins. The entire genome, except for the 5' untranslated region, is highly variable and viruses sequenced from different regions of the world form at least six genotypes and at least 30 subtypes. The virus is difficult to grow in cell culture, but transfection of a hepatoma cell line is possible, and adaptive mutations in the virus genome allow efficient replication in hepatoma cell lines. No neutralizing antibodies have been found, and experimentally infected primates are not immune to superinfection. In humans the incubation period to disease following infection is 6-8 weeks, but about 75% of infections are subclinical and give rise to chronic persistent infection. Of these, some 50% develop chronic liver disease with persistently elevated liver enzymes in serum. About half of the patients with chronic liver disease go on to develop chronic active hepatitis and 5-20% of these will progress to cirrhosis of the liver by five years from onset. There is also a clear link between HCV infection and the development of hepatocellular carcinoma, since up to 75% of such patients have anti-HCV serum antibodies. The development of anti-HCV screening tests has greatly reduced the incidence of HCV infection through transfusions. There is no vaccine and the only available drug for chronic infection is interferon alpha

(2 million units thrice weekly) plus rib-avirin (Virazole) which is effective in 50% of cases during prolonged treatment, although relapses usually occur when the drug is withdrawn.

Synonyms: NANB hepatitis virus; non-A non-B hepatitis virus.

Alter MJ (1997) Hematology 26, 62S Blight KJ et al (2000) Science 290,1972 Lohmann V et al (1999) Science 285, 110 Major ME and Feinstone SM (1997) Hepatology 25,1527

Hepatitis delta virus (HDV) A satellite virus, the only species in the genus Deltavirus. First recognized when a novel antigen (delta antigen) was observed in the nuclei of hepatocytes of some patients with chronic Hepatitis B virus (HBV) infection. Virions are spherical, about 34nm in diameter, with no surface projections. Transmission of HDV is dependent upon HBV, since it uses HBsAg as its own virion coat. The HDV genome is a small single-stranded circular RNA comprised of 1675 nucleotides with about 70% base-pairing so that the RNA forms a largely double-stranded, rod-shaped structure. A single conserved open reading frame in the negative sense encodes the Hepatitis delta antigen, which consists of two protein species: one contains 195 amino acids (24kDa) and the other is identical except for an additional 19 amino acids at the C-terminus (27kDa). Most sera contain equal amounts of the two species of antigen, which appears to function during replication through its nuclear localization and RNA-binding properties. Once inside the nucleus, replication is carried out by the host cell RNA polymerase and is independent of HBV virus. HDV has only been isolated from humans and is widely distributed geographically, with some 5% of HBsAg carriers infected worldwide. Following infection, there is an incubation period of 3-7 weeks before fatigue, anorexia and nausea occur, followed by jaundice and other symptoms of hepatitis. A high proportion (60-70%) of patients with chronic HDV infection develop cirrhosis, and up to 20% develop fulminant hepatitis. No specific treatment is available, but since HDV is dependent upon HBV infection, vaccination against HBV provides protection.

Synonyms: delta agent; delta virus; epidemic hepatitis-associated antigen.

Lai MMC (1995) Annu Rev Biochem 64, 259 Taylor JM (1998) In Virology, vol. 1 of Topley & Wilson's Microbiology and Microbial Infections. Ninth edition, edited by BWJ Mahy and L Collier. London: Arnold, p. 775

hepatitis D virus Synonym for Hepatitis delta virus.

'Hepatitis E-like viruses' A floating genus of positive-sense single-stranded RNA viruses which cause outbreaks and sporadic cases of enterically transmitted hepatitis. The type species is Hepatitis E virus.

Hepatitis E virus (HEV) The type species of the genus 'Hepatitis E-like viruses' which causes acute enterically transmitted epidemics of hepatitis, especially in young to middle-aged persons in Asia, Africa and S America. Large epidemics with many thousands of cases have occurred in India, Burma and Kyrgystan. The virus was molecularly cloned, by the SISPA technique, from virus-enriched bile obtained from experimentally infected cynomolgus monkeys, but so far has not been reliably grown in cell culture. The genome is a 7.5kb single positive-stranded RNA molecule with a 3' poly A tail and a capped 5' terminus (in contrast to most other caliciviruses, which have a VPg covalently attached at the 5' terminus). The non-structural proteins are encoded toward the 5' end, and structural proteins toward the 3' end. Three separate open reading frames are used. ORF1 encodes up to six non-structural proteins, which include a methyltransferase, cys-teine protease, helicase and RNA replicase. There is a 37-base untranslated region between ORF1 and ORF2 which is synthesized as a subgenomic RNA and encodes the structural protein(s) preceded by a signal peptide. Between ORF1 and ORF2 the genome encodes a small protein (123 amino acids) of unknown function in ORF3, which overlaps ORF1 by one base. Screening tests for antibodies are being developed which use peptide or recombinant-expressed antigens. The use of these prototype assays suggests that anti-HEV serum antibody prevalence in the USA population is less than 1%, but it appears to be higher in some endemic areas. Antibodies are also found in a high percentage of wild rats, Rattus norvegicus, in the USA, and the virus appears to be endemic in swine.

Berke T et al (1997) J Med Virol 52, 419 Jameel S et al (1996) J Virol 70,207 Kabrane-Lazizi Y et al (1999) Am J Trop Med Hyg 61, 331

Purdy MA et al (1993) Semin Virol 4, 319 Reyes GR and Baroudy BM (1991) Adv Virus Res 40, 57

hepatitis F virus A novel agent claimed to be responsible for sporadic non-A non-B hepatitis in humans. The infectious material came from French patients, so the F stands for 'French origin'. The genome consists of a double-stranded DNA of ca. 20kb. The particles are infectious in monkeys, conferring immunity. Epidemics have occurred in England, Italy, France, USA and India. These claims need independent confirmation and to date this has not happened.

Hepatitis G virus (HGV-1) An unassigned species in the family Flaviviridae, identified by molecular cloning, expression and immunoreactivity in the plasma of a patient with chronic hepatitis. The genome is 9792 nucleotides long, positive-sense, containing a single, long open reading frame encoding a precursor polyprotein of 2873 amino acids. The genome organization and sequence place the virus within the Flaviviridae, distantly related to Hepatitis C virus and GB viruses A and B. It is so closely related to GB virus C, which was discovered earlier, that it is now referred to as GB virus-C/Hepatitis G virus. The virus appears to have a global distribution and persists in serum of hepatitis patients for at least 7 years. Although there is evidence that the virus is hepatotropic, in the majority of cases it does not cause hepatitis. Current estimates suggest that it may be responsible for 0.3% of transfusion-related hepatitis in the USA.

Hadlock KG et al (1997) Transfusion Med Rev 12,94

Linnen J et al (1996) Science 271, 505 Mushahwar IK (2000) J Med Virol 62, 399 Simons JN et al (1995) Nature, Med 1, 564

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