Hepatitis C Virus Quasi-species Intra-host Evolution

Jean-Michel Pawlotsky.

Department of Bacteriology and Virology and INSERM U99, Henri Mondor Hospital, University of Paris XII, Creteil, France.

Hepatitis C virus (HCV) genome is a 10-kb long single-strand linear RNA molecule. Like for many RNA viruses, the HCV genome is highly variable, due to uncorrected errors made by the RNA-dependent RNA polymerase during replication. HCV replication in human hosts triggers numerous non specific and specific antiviral responses, including immune responses, which exert strong pressures towards viral evolution. The treatment of chronic hepatitis C is based on the administration of interferon (IFN) alpha, a molecule with both non specific antiviral effects and immunomodulatory effects. The administration of IFN provides a model of exacerbation of host-virus interactions, because IFN acts by increasing the antiviral pressure on the virus. Nevertheless, HCV evolution appears to be constrained by various structural and functional features. The genetic evolutions of genomic regions representative of the whole genome upon various conditions and their structural and functional consequences will be described. These regions include : (i) the 5' non coding region, a highly structured and well-conserved region containing a stable stem-loop structure acting as in internal ribosome entry site ; (ii) the hypervariable region 1 (HVR1), a variable region located at the 5' end of the E2 envelope glycoprotein gene that encodes a major neutralizing HCV epitope, a cytotoxic epitope and, possibly, conserved structures involved in the virus life-cycle ; (iii) the non structural 5A (NS5A) protein, that plays a role in the regulation of HCV replication and acts as a transcriptional activator in vitro.

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