With an estimated 170 million infected individuals, hepatitis C virus (HCV) has a major impact on public health. A vaccine protecting against HCV infection is not available, and current antiviral therapies are characterized by limited efficacy, high costs, and substantial side effects. Binding of the virus to the cell surface followed by viral entry is the first step in a cascade of interactions between virus and the target cell that is required for the initiation of infection. Because this step represents a critical determinant of tissue tropism and pathogenesis, it is a major target for host cell responses such as antibody-mediated virus-neutralization-and a promising target for new antiviral therapy. The recent development of novel tissue culture model systems for the study of the first steps of HCV infection has allowed rapid progress in the understanding of the molecular mechanisms of HCV binding and entry. This review summarizes the impact of recently identified viral and host cell factors for HCV attachment and entry. Clinical implications of this important process for the pathogenesis of HCV infection and novel therapeutic interventions are discussed. (HEPATOLOGY 2006;44:527-535.)
W ith an estimated 170 million infected individuals, hepatitis C virus (HCV) has a major impact on public health. 1 A vaccine protecting against HCV infection is not available, and current antiviral therapies are characterized by limited efficacy, high cost, and substantial side effects. 2 HCV is a small enveloped positive-strand RNA virus that has been classified in a separate genus (Hepacivirus) of the Flaviviridae family. In vivo, HCV infects only humans and chimpanzees. Tree shrews and transgenic mice repopulated with human hepatocytes are susceptible to experimental infection. The liver is the primary target organ of HCV infection. Apart from infection of hepatocytes, infection of B cells and dendritic cells has been described. Attachment of the virus to the cell surface followed by viral entry is the first step in a cascade of interactions between virus and the target cell that is required for the initiation of infection. 8 Because this step represents a critical determinant of tissue tropism and pathogenesis, it is a major target for host cell responses-such as antibody-mediated virus-neutralization-and a promising target for a new antiviral therapy.
Model Systems for the Study of Viral Attachment and Entry
To study viral attachment, entry, and infection, several in vitro models have been developed. Inoculation of primary hepatocytes with serum-derived HCV is an elegant way to study HCV infection in vitro. Primary hepatocytes from humans, chimpanzees, or tree shrews can be successfully infected with serum-derived HCV. 9,10 However, limitations of these systems are the low level of HCV replication requiring reverse transcription polymerase chain reaction for detection of viral infection, the variable quality of the human hepatocytes obtained from surgical specimens, and the lack of a well-defined viral inoculum. Furthermore, the lack of suitable methods to measure cell surface-bound HCV have made it difficult to study important mechanisms of viral life cycle such as the attachment of the virion to the host cell, which is usually