title: Transmission of clonal hepatitis C virus genomes reveals the dominant but transitory role of CD8⁺ T cells in early viral evolution.
abstract: The RNA genome of the hepatitis C virus (HCV) diversifies rapidly during the acute phase of infection, but the selective forces that drive this process remain poorly defined. Here we examined whether Darwinian selection pressure imposed by CD8(+) T cells is a dominant force driving early amino acid replacement in HCV viral populations. This question was addressed in two chimpanzees followed for 8 to 10 years after infection with a well-defined inoculum composed of a clonal genotype 1a (isolate H77C) HCV genome. Detailed characterization of CD8(+) T cell responses combined with sequencing of recovered virus at frequent intervals revealed that most acute-phase nonsynonymous mutations were clustered in class I epitopes and appeared much earlier than those in the remainder of the HCV genome. Moreover, the ratio of nonsynonymous to synonymous mutations, a measure of positive selection pressure, was increased 50-fold in class I epitopes compared with the rest of the HCV genome. Finally, some mutation of the clonal H77C genome toward a genotype 1a consensus sequence considered most fit for replication was observed during the acute phase of infection, but the majority of these amino acid substitutions occurred slowly over several years of chronic infection. Together these observations indicate that during acute hepatitis C, virus evolution was driven primarily by positive selection pressure exerted by CD8(+) T cells. This influence of immune pressure on viral evolution appears to subside as chronic infection is established and genetic drift becomes the dominant evolutionary force.
authors: Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Research II Building, Room WA4104, 700 Children's Drive, Columbus, OH 43205, USA.
authors: Benoît
authors: B
authors: Callendret
authors: Jens
authors: J
authors: Bukh
authors: Heather B
authors: HB
authors: Eccleston
authors: Ryan
authors: R
authors: Heksch
authors: Dana L
authors: DL
authors: Hasselschwert
authors: Robert H
authors: RH
authors: Purcell
authors: Austin L
authors: AL
authors: Hughes
authors: Christopher M
authors: CM
authors: Walker
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000821:virology*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D000939:Epitopes / Q000235:genetics; D019143:Evolution, Molecular; D016679:Genome, Viral; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification; D006526:Hepatitis C / Q000276:immunology* / Q000821:virology; D020125:Mutation, Missense; D002679:Pan troglodytes; D018419:Primate Diseases / Q000276:immunology* / Q000821:virology; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D000939:Epitopes