Course and outcome of hepatitis C

Abstract

The hepatitis C virus (HCV) is a small enveloped RNA virus belonging to the family flaviviridae and genus hepacivirus. The HCV RNA genome is 9,600 nucleotides in length and encodes a single polyprotein that is post-translationally cleaved into 10 polypeptides including t3 structural (C, El, and E2) and multiple nonstructural proteins ( [NS] NS2 to NS5). The NS proteins include enzymes necessary for protein processing (proteases) and viral replication (RNA polymerase). The virus replicates at a high rate in the liver and has marked sequence heterogeneity. There are 6 genotypes and more than 90 subtypes of HCV, the most common in the United States being l a and l b (approximately 75%), 2a and 2b (approximately 15%0), and 3 (approximately 7%). Acute hepatitis C is marked by appearance of HCV RNA in serum within 1 to 2 weeks of exposure followed by serum alanine aminotransferase (ALT) elevations, and then symptoms and jaundice. Antibody to HCV (anti-HCV) tends to arise late. In acute resolving hepatitis, HCV RNA is cleared and serum ALT levels fall to normal. However, 55% to 85% of patients do not clear virus, but develop chronic hepatitis C. Chronic hepatitis C is often asymptomatic, but is usually associated with persistent or fluctuating elevations in ALT levels. The chronic sequelae of hepatitis C include progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Extra-hepatic manifestations include sicca syndrome, cryoglobulinemia, glomerulonephritis, and porphyria cutanea tarda. Knowledge of the course and outcome of hepatitis C is important in developing approaches to management and therapy. (HEPATOLOGY 2002;36:S21-S29.) H epatitis C is caused by a small RNA virus that belongs to the family flaviviridae and is the sole member of the genus hepacivirus.1.2 First identified in 1989,"* the hepatitis C virus (HCV) has a singlestranded RNA genome that is approximately 9.6 kilobases in length and encodes a single, large polyprotein of about 3,000 amino acids.5 The HCV-encoded polyprotein is cleaved post-translationally into multiple structural and nonstructural (NS) peptides: structural components consisting of a nucleocapsid core (C) and 2 envelope glycoproteins (El and E2) and the NS proteins being labeled NS2 through NS5 (Fig. l ) dependent RNA polymerase activity essential for RNA viral replication. These enzymatic activities are potential targets for antiviral compounds. The HCV genome also has important and highly conserved 5' and 3' untranslated regions.5-7 The 5' untranslated region has an internal ribosomal entry site essential for initiation of viral protein translation, and the 3' untranslated region has structured RNA elements essential for both viral replication and translation (Fig. 1).There are no robust cell culture systems for propagation of HCV, nor are there simple small animal models of the infection, so that the replicative cycle of the virus has largely been deduced from that of other flaviviruses. Hepatitis C virus replicates in the cytoplasm of hepatocytes where it is not direct...

Entry and replication of recombinant hepatitis C viruses in cell culture

“…The virus responsible for this disease, later called hepatitis C virus (HCV), currently infects chronically around 160 million people worldwide [2]. These are at risk of developing serious liver disease including hepatic steatosis, fibrosis, cirrhosis and ultimately hepatocarcinoma [3]. From the beginning, HCV turned out to be a real challenge for scientists.…”

Development of a high-throughput pyrosequencing assay for monitoring temporal evolution and resistance associated variant emergence in the Hepatitis C virus protease coding-region

“…Approximately 75-85% of infections progress to chronicity, predisposing carriers to an increased risk of developing cirrhosis and hepatocellular carcinoma (Hoofnagle, 2002).…”

Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients

“…Hepatitis C virus (HCV), a human hepatotropic Flaviviridae member not requiring insect vector transmission, may establish chronic replication and is responsible for a heavy burden of long-term disease including chronic hepatitis, cirrhosis, hepatocellular carcinoma, cryoglobulinaemia and vasculitis [1]. The high worldwide prevalence of infection (*170 million cases estimated by the World Health Organization) is associated, at least in part, to the chronic persistent course of infection that ensues in the majority of acutely infected patients (>85%) leading to continuous highlevel viral replication [2].…”