title: CSF/plasma HIV-1 RNA discordance even at low levels is associated with up-regulation of host inflammatory mediators in CSF.
abstract: HIV-1 RNA can be found at higher levels in cerebrospinal fluid (CSF) than in plasma, termed CSF/plasma discordance. The clinical significance of CSF/plasma discordance is not known and the degree of discordance considered important varies. We aimed to determine whether a panel of CSF cytokines, chemokines and associated mediators were raised in patients with CSF/plasma discordance at different levels.
  
  
  
  A nested case-control study of 40 CSF samples from the PARTITION study. We used a cytometric bead array to measure CSF mediator concentrations in 19 discordant and 21 non-discordant samples matched for plasma HIV-1 RNA. Discordant samples were subdivided into 'high discordance' (>1log10) and 'low discordance' (0.5-1log10, or ultrasensitive discordance). CSF mediators significant in univariate analysis went forward to two-way unsupervised hierarchical clustering based on the patterns of relative mediator concentrations.
  
  
  
  In univariate analysis 19 of 21 CSF mediators were significantly higher in discordant than non-discordant samples. There were no significant differences between samples with high versus low discordance. The samples grouped into two clusters which corresponded to CSF/plasma discordance (p<0.0001). In cluster one all mediators had relatively high abundance; this included 18 discordant samples and three non-discordant samples. In cluster two all mediators had relatively low abundance; this included 18 non-discordant samples and one non-discordant sample with ultrasensitive discordance only.
  
  
  
  CSF/plasma discordance is associated with potentially damaging neuroinflammatory process. Patients with discordance at lower levels (ie. 0.5-1log10) should also be investigated as mediator profiles were similar to those with discordance >1log10. Sensitive testing may have a role to determine whether ultrasensitive discordance is present in those with low level CSF escape.
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, UK; Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK; Royal Liverpool and Broadgreen University Hospitals NHS Trust, UK. Electronic address: s.nightingale@liv.ac.uk.
authors.forename: Sam
authors.initials: S
authors.lastname: Nightingale
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, UK; Walton Centre for Neurology and Neurosurgery, Liverpool, UK.
authors.forename: Benedict D
authors.initials: BD
authors.lastname: Michael
authors.affiliation: Brighton and Sussex University Hospitals NHS Trust, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Fisher
authors.affiliation: St Marys' Hospital, Imperial College Heathcare NHS Trust, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Winston
authors.affiliation: St Stephen's AIDS Research Trust and Chelsea and Westminster Hospital NHS Foundation Trust, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Nelson
authors.affiliation: Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Taylor
authors.affiliation: North Manchester General Hospital, Pennine Acute Hospitals NHS Trust, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ustianowski
authors.affiliation: North Middlesex University Hospital NHS Trust, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ainsworth
authors.affiliation: Research Department of Infection and Population Health, University College London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Gilson
authors.affiliation: Research Department of Infection and Population Health, University College London, UK.
authors.forename: Lewis
authors.initials: L
authors.lastname: Haddow
authors.affiliation: Victoria Royal Infirmary, Newcastle upon Tyne Hospitals NHS Trust, UK.
authors.forename: Edmund
authors.initials: E
authors.lastname: Ong
authors.affiliation: Royal Infirmary of Edinburgh, NHS Lothian, UK.
authors.forename: Clifford
authors.initials: C
authors.lastname: Leen
authors.affiliation: Leeds General Infirmary, Leeds Teaching Hosptials NHS Trust, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Minton
authors.affiliation: Kings College Hospital NHS Foundation Trust, London, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Post
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, UK.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Beloukas
authors.affiliation: Vaccine Evaluation Unit at the Health Protection Agency (HPA) North West, Manchester, UK.
authors.forename: Ray
authors.initials: R
authors.lastname: Borrow
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, UK.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Geretti
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, UK; Walton Centre for Neurology and Neurosurgery, Liverpool, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Solomon
mesh_terms: D000328:Adult; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid; D015497:HIV-1; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012367:RNA, Viral / Q000096:biosynthesis / Q000134:cerebrospinal fluid
chemical_list: D018836:Inflammation Mediators; D012367:RNA, Viral
keywords: CSF escape; Cerebrospinal fluid; HIV; Inflammation; Sanctuary site