How does hepatitis C virus enter cells?

Abstract

The World Health Organization estimates that 170 million people, 3% of the world population, are infected with hepatitis C virus (HCV) [1]. The majority of those infected (55-85%) fail to clear the virus and become chronic carriers manifested by the persistent presence of detectable virus in the serum [2]. The clinical course of chronic hepatitis C is highly variable ranging from mild hepatitis (inflammation of the liver), fibrosis (scaring of the liver), cirrhosis (end-stage fibrosis) to hepatocellular carcinoma (liver cancer). Liver damage is not directly caused by the virus, but by the interplay between the virus and the immune system that results in the replacement of healthy liver tissue with fibrous scar tissue. About 20% of patients with chronic hepatitis C will develop liver cirrhosis within 20 years. Once cirrhosis is established, the rate of hepatocellular cancer development is 1-4% per year [3]. The standard treatment for chronic HCV infection is pegylated a-interferon in combination with the nucleoside analogue ribavirin. About 55% of patients respond to the therapy and show a sustained reduction in viral titer [4]. Few treatment options exist for nonresponders. Ribavarin and a-interferon have general antiviral properties not specifically related to HCV. Drugs interfering specifically with HCV RNA replication or translation and processing of HCV proteins are not available yet, but a few promising candidates are in clinical testing [5,6].Since the discovery of HCV in 1989, the major bottleneck in HCV research has been the lack of a robust and reliable cell culture system for the propagation of the virus, and the absence of a nonprimate animal model. While cultured liver cells can be infected with clinical HCV isolates, the process has been inefficient, transient and not always reproducible [7]. Our current knowledge about the mechanism of viral cell entry comes from several different approaches including vaccination of chimpanzees, structural studies of Hepatitis C virus (HCV) exists in different forms in the circulation of infected people: lipoprotein bound and lipoprotein free, enveloped and nonenveloped. Viral particles with the highest infectivity are associated with lipoproteins, whereas lipoprotein-free virions are poorly infectious. The detection of HCV's envelope proteins E1 and E2 in lipoprotein-associated virions has been challenging. Because lipoproteins are readily endocytosed, some forms of HCV might utilize their association with lipoproteins rather than E1 and E2 for cell attachment and internalization. However, vaccination of chimpanzees with recombinant envelope proteins protected the animals from hepatitis C infection, suggesting an important role for E1 and E2 in cell entry. It seems possible that different forms of HCV use different receptors to attach to and enter cells. The putative receptors and the assays used for their validation are discussed in this review.

Contribution of Redox Status to Hepatitis C Virus E2 Envelope Protein Function and Antigenicity

“…As shown with serum-derived virus, HCV uses various processes to enter target cells, and HCVpp infection of Huh7-cells is a surrogate model for most entry pathways, including the CD81 route used here, its sole lack being entry mediated by virus when associated with lipoproteins (11,12,30,(35)(36)(37)(38)(39). In this system, CD81 and E2 clearly have a major role because anti-E2 antibodies and soluble CD81 interfere with virus entry (24,39).…”

Dysmetabolic changes associated with HCV: a distinct syndrome?

“…Of interest, removal of lipoproteins from infected sera by apheresis reduced HCV RNA levels by 77% suggesting that the majority of infecting viral particles are associated with lipoproteins whereas lipoprotein-free virions are poorly infectious [79]. Various HCV receptor candidates have been proposed, including CD 81 and LDL receptors [80]. In vitro binding and endocytosis of HCV is limited by LDL particles via competitive inhibition [81].…”

Correlation of the Tight Junction-like Distribution of Claudin-1 to the Cellular Tropism of Hepatitis C Virus

“…In nature, the virus may exist in several forms: enveloped lipoprotein-free virus, enveloped lipoprotein-associated virus, non-enveloped lipoprotein-free virus, and non-enveloped lipoprotein-associated virus (1). While the nature of these different forms remains elusive, they may infect cells via different means (1). Importantly, pseudoviral particles that consist of an HIV core and HCV E1 and E2 (i.e.…”