title: Persistent hepatitis C virus infection in vitro: coevolution of virus and host.
abstract: The virological and cellular consequences of persistent hepatitis C virus (HCV) infection have been elusive due to the absence of the requisite experimental systems. Here, we report the establishment and the characteristics of persistent in vitro infection of human hepatoma-derived cells by a recently described HCV genotype 2a infectious molecular clone. Persistent in vitro infection was characterized by the selection of viral variants that displayed accelerated expansion kinetics, higher peak titers, and increased buoyant densities. Sequencing analysis revealed the selection of a single adaptive mutation in the HCV E2 envelope protein that was largely responsible for the variant phenotype. In parallel, as the virus became more aggressive, cells that were resistant to infection emerged, displaying escape mechanisms operative at the level of viral entry, HCV RNA replication, or both. Collectively, these results reveal the existence of coevolutionary events during persistent HCV infection that favor survival of both virus and host.
authors.affiliation: Department of Molecular and Experimental Medicine, SBR-10, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhong
authors.forename: Pablo
authors.initials: P
authors.lastname: Gastaminza
authors.forename: Josan
authors.initials: J
authors.lastname: Chung
authors.forename: Zania
authors.initials: Z
authors.lastname: Stamataki
authors.forename: Masanori
authors.initials: M
authors.lastname: Isogawa
authors.forename: Guofeng
authors.initials: G
authors.lastname: Cheng
authors.forename: Jane A
authors.initials: JA
authors.lastname: McKeating
authors.forename: Francis V
authors.initials: FV
authors.lastname: Chisari
mesh_terms: D000220:Adaptation, Biological; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D020125:Mutation, Missense; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D017422:Sequence Analysis, DNA; D014759:Viral Envelope Proteins; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: D012367:RNA, Viral; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus