Hepatitis C Virus
2. Replication Scheme
The primary host cell is the hepatocyte but replication has also been described for peripheral blood mononuclear cells (PBMCs) as well as several B and T cell lines. Upon binding of HCV to the host cell the viral RNA is released from the nucleocapsid into the cytoplasm presumably in a pH-dependent manner. Directed by the IRES in the 5' NTR, the viral genome is translated and the resulting polyprotein is proteolytically cleaved into individual proteins. Most, if not all, of these proteins form a higher-order multi-protein complex tightly associated with intracellular membranes.
Within this complex the positive strand RNA genome is copied into a negative strand RNA intermediate that in turn serves as a template for synthesis of excess amounts of positive strand progeny. These positive strands may be used either for synthesis of new negative strands, for translation or be encapsidated into virus particles. The fact that the E-proteins are not transported beyond the cis-Golgi suggests that viral nucleocapsids acquire their envelope by budding into the lumen of intracellular membrane compartments. In this case the virus may be exported via the constitutive secretory pathway.
HCV particles bind to the host cell via a specific interaction between the HCV envelope glycoproteins and a yet unknown cellular receptor complex that probably includes CD81. Bound particles appear to be internalized by receptor-mediated endocytosis. After the viral genome is liberated from the nucleocapsid (uncoating) and translated at the rough ER, NS4B (perhaps in conjunction with other viral and cellular factors) induces the formation of membranous vesicles (refered to as membranous web). These membranes are supposed to serve as scaffolds for the viral replication complex. After genome amplification and HCV protein expression, progeny virions are assembled. The site of virus particle formation has not yet been identified. It may take place at intracellular membranes derived from the ER or the Golgi compartment. Newly produced virus particles may leave the host cell by the constitutive secretory pathway. The upper right panel of the figure shows a schematic representation of an HCV particle. Note that the envelope proteins E1 and E2 are drawn according to the proposed structure and orientation of the TBEV envelope proteins M and E, respectively (Yagnik et al., 2000). The lower right panel shows a model for the synthesis of negative strand (-) and positive strand (+) progeny RNA via a double stranded replicative form (RF) and a replicative intermediate (RI).