title: Sequential bottlenecks drive viral evolution in early acute hepatitis C virus infection.
abstract: Hepatitis C is a pandemic human RNA virus, which commonly causes chronic infection and liver disease. The characterization of viral populations that successfully initiate infection, and also those that drive progression to chronicity is instrumental for understanding pathogenesis and vaccine design. A comprehensive and longitudinal analysis of the viral population was conducted in four subjects followed from very early acute infection to resolution of disease outcome. By means of next generation sequencing (NGS) and standard cloning/Sanger sequencing, genetic diversity and viral variants were quantified over the course of the infection at frequencies as low as 0.1%. Phylogenetic analysis of reassembled viral variants revealed acute infection was dominated by two sequential bottleneck events, irrespective of subsequent chronicity or clearance. The first bottleneck was associated with transmission, with one to two viral variants successfully establishing infection. The second occurred approximately 100 days post-infection, and was characterized by a decline in viral diversity. In the two subjects who developed chronic infection, this second bottleneck was followed by the emergence of a new viral population, which evolved from the founder variants via a selective sweep with fixation in a small number of mutated sites. The diversity at sites with non-synonymous mutation was higher in predicted cytotoxic T cell epitopes, suggesting immune-driven evolution. These results provide the first detailed analysis of early within-host evolution of HCV, indicating strong selective forces limit viral evolution in the acute phase of infection.
authors.affiliation: School of Medical Sciences, University of New South Wales, Australia.
authors.forename: Rowena A
authors.initials: RA
authors.lastname: Bull
authors.forename: Fabio
authors.initials: F
authors.lastname: Luciani
authors.forename: Kerensa
authors.initials: K
authors.lastname: McElroy
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaudieri
authors.forename: Son T
authors.initials: ST
authors.lastname: Pham
authors.forename: Abha
authors.initials: A
authors.lastname: Chopra
authors.forename: Barbara
authors.initials: B
authors.lastname: Cameron
authors.forename: Lisa
authors.initials: L
authors.lastname: Maher
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Dore
authors.forename: Peter A
authors.initials: PA
authors.lastname: White
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Lloyd
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000208:Acute Disease; D000328:Adult; D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D019143:Evolution, Molecular; D005260:Female; D005814:Genes, Viral; D005819:Genetic Markers; D014644:Genetic Variation; D006239:Haplotypes; D016174:Hepacivirus / Q000235:genetics* / Q000302:isolation & purification; D006526:Hepatitis C / Q000276:immunology* / Q000635:transmission / Q000821:virology*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012367:RNA, Viral / Q000235:genetics / Q000302:isolation & purification; D017422:Sequence Analysis, DNA; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D005819:Genetic Markers; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase