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THE MOLECULAR BIOLOGY OF HEPATITIS C VIRUS

1999; Elsevier BV; Volume: 3; Issue: 4 Linguagem: Inglês

10.1016/s1089-3261(05)70234-8

1557-8224

Xavier Forns, Jens Bukh,

Liver Disease Diagnosis and Treatment

Hepatitis C virus (HCV) is a member of the Flaviviridae family.124 The Flaviviridae family of viruses are associated with human and animal diseases and encompass at least three different genera: pestiviruses, such as bovine viral diarrhea virus and classic swine fever virus that cause disease in cattle and pigs, respectively; flaviviruses, the most important cause of arthropod-transmitted viral diseases, for example, dengue fever and yellow fever; and hepacivirus, whose sole member is HCV. The GB viruses, which are also members of the Flaviviridae, are most closely related to HCV and infect humans and monkeys.13, 89, 144, 145 One of the signature characteristics of HCV is its genetic heterogeneity.16 Thus, HCV isolates from around the world have been divided into six major genotypes and more than 100 subtypes.16, 45 Moreover, genetic heterogeneity of HCV within infected individuals is manifested as a mixture of closely related but distinct genomes called a quasispecies.16, 100 More than 2% of the world population is chronically infected with HCV.66, 120, 170 In developed countries, HCV is the main cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma; HCV-related end-stage liver disease is now the leading reason for liver transplantation.109 Hepatitis C virus infection is also associated with a number of extrahepatic diseases, such as cryoglobulinemia and glomerulonephritis.65 The most important feature of HCV infection is its high rate of chronicity. More than 80% of HCV-infected individuals develop a chronic infection.66 Unfortunately, treatment of chronic hepatitis C with interferon (IFN), the principal recognized therapeutic agent, succeeds only in 20% of the cases.109 The response rate is even lower in patients infected with genotype 1 HCV. Recently, a combination treatment of IFN and ribavirin has achieved higher response rates both in patients infected with genotype 1 and in patients infected with other genotypes.101, 118 Despite the heartening progress achieved in treating chronic hepatitis C with combination therapy, the overall response rate in these patients is still below 50%. A better understanding of the molecular biology of HCV has highlighted targets for new therapeutic strategies. The genetic heterogeneity of HCV is a major confounding factor; thus, the design of effective drugs might be facilitated by targeting conserved regions of HCV. Drugs directed against conserved sequences of the 5′ untranslated region (UTR)8, 53, 123, 130 and the serine-protease domain within NS328, 84 have already been tested in vitro. The lack of a reliable cell culture system or small animal model for HCV (the chimpanzee is the only recognized animal model) presents significant obstacles for the study of these new therapeutic agents. The recent availability of infectious HCV cDNA clones80, 172, 174 may facilitate the establishment of useful in vitro replication systems.