title: Exceptional Heterogeneity in Viral Evolutionary Dynamics Characterises Chronic Hepatitis C Virus Infection.
abstract: The treatment of HCV infection has seen significant progress, particularly since the approval of new direct-acting antiviral drugs. However these clinical achievements have been made despite an incomplete understanding of HCV replication and within-host evolution, especially compared with HIV-1. Here, we undertake a comprehensive analysis of HCV within-host evolution during chronic infection by investigating over 4000 viral sequences sampled longitudinally from 15 HCV-infected patients. We compare our HCV results to those from a well-studied HIV-1 cohort, revealing key differences in the evolutionary behaviour of these two chronic-infecting pathogens. Notably, we find an exceptional level of heterogeneity in the molecular evolution of HCV, both within and among infected individuals. Furthermore, these patterns are associated with the long-term maintenance of viral lineages within patients, which fluctuate in relative frequency in peripheral blood. Together, our findings demonstrate that HCV replication behavior is complex and likely comprises multiple viral subpopulations with distinct evolutionary dynamics. The presence of a structured viral population can explain apparent paradoxes in chronic HCV infection, such as rapid fluctuations in viral diversity and the reappearance of viral strains years after their initial detection.
authors.affiliation: Department of Zoology, University of Oxford, Oxford, United Kingdom.
authors.forename: Jayna
authors.identifier: 0000-0001-8538-4995
authors.initials: J
authors.lastname: Raghwani
authors.affiliation: BioInfoExperts, Thibodaux, Los Angeles, California, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rose
authors.affiliation: Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
authors.forename: Isabelle
authors.identifier: 0000-0002-3310-2578
authors.initials: I
authors.lastname: Sheridan
authors.affiliation: Department of Microbiology and Immunology, Rega Institute, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lemey
authors.affiliation: Departments of Biomathematics, Biostatistics, Human Genetics, University of California, Los Angeles, California, United States of America.
authors.forename: Marc A
authors.identifier: 0000-0001-9818-479X
authors.initials: MA
authors.lastname: Suchard
authors.affiliation: Clinic of Infectious Diseases, University of Foggia, Foggia, Italy.
authors.forename: Teresa
authors.identifier: 0000-0002-4342-6904
authors.initials: T
authors.lastname: Santantonio
authors.affiliation: Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Farci
authors.affiliation: Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
authors.forename: Paul
authors.identifier: 0000-0003-4307-9161
authors.initials: P
authors.lastname: Klenerman
authors.affiliation: Department of Zoology, University of Oxford, Oxford, United Kingdom.
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Pybus
mesh_terms: D019143:Evolution, Molecular; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000235:genetics; D015497:HIV-1 / Q000235:genetics; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000235:genetics*; D006801:Humans; D008297:Male; D014779:Virus Replication