Hepatitis C virus replication cycle

Abstract

Ecole Normale Superieure de Lyon,Lyon F-69007, FranceHepatitis C virus (HCV) is a positive strand RNA virus forming thegenus Hepacivirus in the Flaviviridae family. Replication of HCVstarts with the virus binding to hepatocytes, which are the pri-mary, if not exclusive host cells. HCV entry is a multi-step andslow process (Panel 1). Interactions between HCV E1–E2 enve-lope glycoproteins and glycosaminoglycans (GAGs) contributeto primary binding of the virus particles to host cells. Owing tothe association of HCV with (very) low-density-lipoproteins[(V)LDL] [1], the LDL receptor (LDLr) has also been proposed asa capture molecule. Upon this initial engagement, the scavengerreceptor BI (SR-BI), the CD81 tetraspanin, together with the tightjunction proteins Claudin-1 (CLDN-1) and Occludin (OCLN) syn-ergistically contribute to HCV uptake in a clathrin-dependentmanner [2]. Additional serum factors, e.g., high-density-lipopro-tein, promote entry by increasing uptake kinetics throughinteraction with SR-BI [3]. HCV entry appears to occur in a pH-dependent manner, whereby the low endosomal pH induces con-formational rearrangement of HCV glycoproteins, leading tofusion of the viral and endosomal membranes and subsequentuncoating.Viral RNA released into the cytoplasm is translated via aninternal ribosome entry site (IRES) located in the 5