title: Within-host evolution results in antigenically distinct GII.4 noroviruses.
abstract: Genogroup II, genotype 4 (GII.4) noroviruses are known to rapidly evolve, with the emergence of a new primary strain every 2 to 4 years as herd immunity to the previously circulating strain is overcome. Because viral genetic diversity is higher in chronic than in acute infection, chronically infected immunocompromised people have been hypothesized to be a potential source for new epidemic GII.4 strains. However, while some capsid protein residues are under positive selection and undergo patterned changes in sequence variation over time, the relationships between genetic variation and antigenic variation remains unknown. Based on previously published GII.4 strains from a chronically infected individual, we synthetically reconstructed virus-like particles (VLPs) representing early and late isolates from a small-bowel transplant patient chronically infected with norovirus, as well as the parental GII.4-2006b strain. We demonstrate that intrahost GII.4 evolution results in the emergence of antigenically distinct strains over time, comparable to the variation noted between the chronologically predominant GII.4 strains GII.4-2006b and GII.4-2009. Our data suggest that in some individuals the evolution that occurs during a chronic norovirus infection overlaps with changing antigenic epitopes that are associated with successive outbreak strains and may select for isolates that are potentially able to escape herd immunity from earlier isolates.
  
  
  OBJECTIVE
  Noroviruses are agents of gastrointestinal illness, infecting an estimated 21 million people per year in the United States alone. In healthy individuals, symptomatic infection typically resolves within 24 to 48 h. However, symptoms may persist for years in immunocompromised individuals, and development of successful treatments for these patients is a continuing challenge. This work is relevant to the design of successful norovirus therapeutics for chronically infected patients; provides support for previous assertions that chronically infected individuals may serve as reservoirs for new, antigenically unique emergent strains; and furthers our understanding of genogroup II, genotype 4 (GII.4) norovirus immune-driven molecular evolution.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Kari
authors.initials: K
authors.lastname: Debbink
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Lindesmith
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Martin T
authors.initials: MT
authors.lastname: Ferris
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Jesica
authors.initials: J
authors.lastname: Swanstrom
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Beltramello
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland Humabs Biomed SA, Bellinzona, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Corti
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland Institute of Microbiology, ETH Zurich, Zurich, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lanzavecchia
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA rbaric@sph.unc.edu.
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Baric
mesh_terms: D000595:Amino Acid Sequence; D000914:Antibodies, Viral / Q000276:immunology; D000940:Antigenic Variation / Q000276:immunology*; D005075:Biological Evolution; D017250:Caliciviridae Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology*; D036022:Capsid Proteins / Q000276:immunology*; D004196:Disease Outbreaks / Q000517:prevention & control; D000939:Epitopes / Q000276:immunology; D005759:Gastroenteritis / Q000276:immunology / Q000517:prevention & control / Q000821:virology*; D006801:Humans; D016867:Immunocompromised Host / Q000276:immunology*; D008969:Molecular Sequence Data; D029322:Norovirus / Q000276:immunology* / Q000302:isolation & purification; D017386:Sequence Homology, Amino Acid; D058425:Vaccines, Virus-Like Particle / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000914:Antibodies, Viral; D036022:Capsid Proteins; D000939:Epitopes; D058425:Vaccines, Virus-Like Particle