title: Deep sequencing of hepatitis C virus reveals genetic compartmentalization in cerebrospinal fluid from cognitively impaired patients.
abstract: Hepatitis C virus (HCV) causes neuropsychiatric impairment and fatigue with recent studies suggesting HCV invasion of the central nervous system (CNS). Our previous finding that endothelial cells from the blood-brain barrier support HCV infection warrants further investigation to elucidate whether the CNS can serve as a reservoir for independent HCV evolution.
  
  
  
  Cerebrospinal fluid (CSF) and plasma from six HCV-infected patients without liver disease or co-morbidities together with plasma from six healthy subjects were profiled for markers of immune activation and viral quasispecies measured by deep sequencing. Unsupervised data analyses were used to identify any associations between cytokine activation markers and clinical outcomes.
  
  
  
  Four of six HCV-infected patients showed significant evidence of cognitive dysfunction and fatigue. Deep sequencing revealed independent viral evolution within the CNS of two cognitively impaired patients. Principal component analysis of peripheral cytokines demonstrated that individuals without cognitive impairment clustered together while a distinct cytokine pattern emerged with patients exhibiting cognitive dysfunction and fatigue.
  
  
  
  Deep sequencing demonstrated unique viral variants in the CSF of two cognitively impaired patients consistent with CNS replication or sequestration. Meanwhile, compartmentalization was absent in infected patients with no neurocognitive impairment. Examination of cytokine profiles in HCV-infected patients with cognitive dysfunction revealed elevated peripheral cytokine levels resulting in a distinct cytokine profile that may be related to cognitive impairment or viral penetration into the CNS. Further studies to determine the significance of unique HCV variants within the CNS are warranted.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
authors.forename: Damien C
authors.initials: DC
authors.lastname: Tully
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.|Department of Affective Disorders, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Hjerrild
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Leutscher
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Signe G
authors.initials: SG
authors.lastname: Renvillard
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
authors.forename: Colin B
authors.initials: CB
authors.lastname: Ogilvie
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bean
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.|Department of Affective Disorders, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Poul
authors.initials: P
authors.lastname: Videbech
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.affiliation: Centre for Human Virology, University of Birmingham, Birmingham, UK.
authors.forename: Jane A
authors.initials: JA
authors.lastname: McKeating
authors.affiliation: Centre for Human Virology, University of Birmingham, Birmingham, UK. nicola.fletcher@ucdconnect.ie.|Veterinary Sciences Centre, University College Dublin, Dublin 4, Ireland. nicola.fletcher@ucdconnect.ie.
authors.forename: Nicola F
authors.initials: NF
authors.lastname: Fletcher
mesh_terms: D000328:Adult; D001812:Blood-Brain Barrier / Q000821:virology; D016022:Case-Control Studies; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000150:complications / Q000821:virology; D016207:Cytokines / Q000097:blood / Q000134:cerebrospinal fluid*; D003718:Denmark; D005221:Fatigue / Q000209:etiology / Q000821:virology; D005260:Female; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000134:cerebrospinal fluid* / Q000150:complications; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D012367:RNA, Viral / Q000097:blood / Q000134:cerebrospinal fluid*
chemical_list: D016207:Cytokines; D012367:RNA, Viral
keywords: brain; cytokine; hepatitis C virus; inflammation; quasispecies