Structural biology of hepatitis C virus☆

HCV genome and polyprotein processing

HCV is a small-enveloped virus containing a positive-sense, single-stranded RNA [5]. Analysis of its genome allowed its classification in the separate genus hepacivirus in the Flaviviridae family that contains the two other genera pestivirus and flavivirus [6]. Flaviviridae also include yet unclassified viruses designated GB viruses A, B and C. GBV-B, a hepatotropic virus that infects tamarins, is the most closely related to HCV.

HCV contains a genome of approximately 9600 nucleotides (nt)

HCV variability

HCV genome shows remarkable sequence variation because of the lack of proofreading activity of the NS5B RNA-dependent RNA polymerase and the high viral turnover rate [16]. Thus, more than 90 genotypes were identified on the basis of nucleic sequence identity around the world [17], [18]. To date, the complete nucleotide sequences of 18 different genotypes have been reported. Each genotype regularly shows more than 20% differences at the nucleotide level and about 15% at the amino acid level, but

HCV life cycle

Hepatocytes appear to be the major site of HCV replication, but peripheral blood mononuclear cells (PBMC) and lymph nodes are also natural HCV targets. Because of the lack of convenient in vitro tissue culture systems for efficient virus propagation in such cells, the current understanding of the molecular mechanisms of HCV replication is mainly based on characterization of recombinant proteins and analogies to other positive-strand RNA viruses of Flaviviridae. The HCV replication cycle remains

HCV morphology and structural proteins

By analogy to closely related flaviviruses of (Dengue virus [27] and tick-borne encephalitis virus [28] and alphaviruses—Semliki Forest virus, Sindbis virus—of known structure, HCV virus is thought to adopt an icosahedral structure with envelope glycoproteins E1 and E2 embedded into the host cell-derived lipid envelope. Underneath the envelope should be the nucleocapsid, presumably composed of multiple copies of core forming the internal viral coat that encapsulates the genomic RNA. Direct

Future directions

The lack of a complete cell culture system for HCV replication remains a major complication for further understanding of the structure–function–pathogenesis relationships, new antiviral target identification, and antiviral development of HCV components. But, in part because of replicons [74], [101] that should allow antiviral drug-screening, and with the knowledge of three-dimensional structure of HCV proteinase, helicase, and RNA polymerase, one can reasonably assume that the major efforts

Acknowledgements

The author gratefully acknowledges Drs Jean Dubuisson, Darius Moradpour, Jean-Pierre Lavergne, Jean-Michel Pawlotsky, and Felix Rey for stimulating discussions.