title: Elucidation of hepatitis C virus transmission and early diversification by single genome sequencing.
abstract: A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures.
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Mark B
authors.initials: MB
authors.lastname: Stoddard
authors.forename: Shuyi
authors.initials: S
authors.lastname: Wang
authors.forename: Lily M
authors.initials: LM
authors.lastname: Blair
authors.forename: Elena E
authors.initials: EE
authors.lastname: Giorgi
authors.forename: Erica H
authors.initials: EH
authors.lastname: Parrish
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Learn
authors.forename: Peter
authors.initials: P
authors.lastname: Hraber
authors.forename: Paul A
authors.initials: PA
authors.lastname: Goepfert
authors.forename: Michael S
authors.initials: MS
authors.lastname: Saag
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Denny
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Ruy M
authors.initials: RM
authors.lastname: Ribeiro
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
authors.forename: Bette T
authors.initials: BT
authors.lastname: Korber
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Bhattacharya
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
mesh_terms: D000208:Acute Disease; D005260:Female; D016679:Genome, Viral / Q000235:genetics* / Q000276:immunology; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics* / Q000276:immunology / Q000635:transmission*; D054884:Host-Pathogen Interactions; D006801:Humans; D008297:Male; D012367:RNA, Viral / Q000235:genetics* / Q000276:immunology; D017423:Sequence Analysis, RNA
chemical_list: D012367:RNA, Viral