CSF/plasma HIV-1 RNA discordance even at low levels is associated with up-regulation of host inflammatory mediators in CSF

Sam Nightingale; Benedict D Michael; Martin Fisher; Alan Winston; Mark Nelson; Steven Taylor; Andrew Ustianowski; Jonathan Ainsworth; Richard Gilson; Lewis Haddow; Edmund Ong; Clifford Leen; Jane Minton; Frank Post; Apostolos Beloukas; Ray Borrow; Munir Pirmohamed; Anna Maria Geretti; Saye Khoo; Tom Solomon

doi:10.1016/j.cyto.2016.04.004

CSF/plasma HIV-1 RNA discordance even at low levels is associated with up-regulation of host inflammatory mediators in CSF

Cytokine. 2016 Jul:83:139-146. doi: 10.1016/j.cyto.2016.04.004. Epub 2016 Apr 28.

Authors

Sam Nightingale¹, Benedict D Michael², Martin Fisher³, Alan Winston⁴, Mark Nelson⁵, Steven Taylor⁶, Andrew Ustianowski⁷, Jonathan Ainsworth⁸, Richard Gilson⁹, Lewis Haddow⁹, Edmund Ong¹⁰, Clifford Leen¹¹, Jane Minton¹², Frank Post¹³, Apostolos Beloukas¹⁴, Ray Borrow¹⁵, Munir Pirmohamed¹⁶, Anna Maria Geretti¹⁴, Saye Khoo¹⁶, Tom Solomon²

Affiliations

¹ 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.
² Institute of Infection and Global Health, University of Liverpool, UK; Walton Centre for Neurology and Neurosurgery, Liverpool, UK.
³ Brighton and Sussex University Hospitals NHS Trust, UK.
⁴ St Marys' Hospital, Imperial College Heathcare NHS Trust, London, UK.
⁵ St Stephen's AIDS Research Trust and Chelsea and Westminster Hospital NHS Foundation Trust, UK.
⁶ Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, UK.
⁷ North Manchester General Hospital, Pennine Acute Hospitals NHS Trust, UK.
⁸ North Middlesex University Hospital NHS Trust, UK.
⁹ Research Department of Infection and Population Health, University College London, UK.
¹⁰ Victoria Royal Infirmary, Newcastle upon Tyne Hospitals NHS Trust, UK.
¹¹ Royal Infirmary of Edinburgh, NHS Lothian, UK.
¹² Leeds General Infirmary, Leeds Teaching Hosptials NHS Trust, UK.
¹³ Kings College Hospital NHS Foundation Trust, London, UK.
¹⁴ Institute of Infection and Global Health, University of Liverpool, UK.
¹⁵ Vaccine Evaluation Unit at the Health Protection Agency (HPA) North West, Manchester, UK.
¹⁶ Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: CSF escape; Cerebrospinal fluid; HIV; Inflammation; Sanctuary site.

Publication types

Clinical Trial
Multicenter Study

MeSH terms

Adult
Female
HIV Infections* / blood
HIV Infections* / cerebrospinal fluid
HIV-1*
Humans
Inflammation Mediators* / blood
Inflammation Mediators* / cerebrospinal fluid
Male
Middle Aged
Prospective Studies
RNA, Viral* / biosynthesis
RNA, Viral* / cerebrospinal fluid

Substances

Inflammation Mediators
RNA, Viral

Abstract

Publication types

MeSH terms

Substances

Grants and funding