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

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

Sam Nightingale  1 , Benedict D Michael  2 , Martin Fisher  3 , Alan Winston  4 , Mark Nelson  5 , Steven Taylor  6 , Andrew Ustianowski  7 , Jonathan Ainsworth  8 , Richard Gilson  9 , Lewis Haddow  9 , Edmund Ong  10 , Clifford Leen  11 , Jane Minton  12 , Frank Post  13 , Apostolos Beloukas  14 , Ray Borrow  15 , Munir Pirmohamed  16 , Anna Maria Geretti  14 , Saye Khoo  16 , Tom Solomon  2
Affiliations
Free PMC article
Clinical Trial

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

Sam Nightingale et al. Cytokine. 2016 Jul.
Free PMC article

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.

Figures

Fig. 1
Fig. 1
Flow-chart of groups described in analysis.
Fig. 2
Fig. 2
HIV-1 RNA in plasma and CSF in discordant (disc) and non-discordant (non-disc) groups.
Fig. 3
Fig. 3
Relationship of CXCL10, CCL3, VCAM and TNFR2 concentration between groups. CXCL10, CCL3, VCAM and TNFR2 concentration (Fig. 1a–d respectively) were significantly higher in discordant versus non-discordant samples. No significant differences were observed between samples with high (CSF >1log10 plasma) versus low (CSF 0.5–1log10 plasma or ultrasensitive discordance) degrees of discordance. Samples with ultrasensitive discordance are represented with an open circle. Mediator concentrations correlated with CSF HIV-1 RNA (Fig. 1e–h). Non-disc, non-discordant; Low-disc, low-discordant; High-disc, high-discordant; ns, not significant; CXCL10, inducible protein 10; VCAM, vascular cell adhesion molecule; CCL3, monocyte inflammatory protein 1a; TNFR2, tumour necrosis factor receptor 2.
Fig. 4
Fig. 4
A heat map displaying the relative concentration of 19 mediators in samples with and without CSF/plasma discordance. Samples and mediators were organised via an unsupervised hierarchical clustering algorithm along the horizontal and vertical axes respectively. Twenty-one samples without discordance are labeled on the x-axis with the symbol “o”. Nineteen samples with discordance are indicated by the symbol “+”; discordant samples with CSF HIV-1 RNA >1log10 plasma are labeled “+++” (n = 11), CSF 0.5–1log10 plasma are labeled “++” (n = 5) and those with ultrasensitive discordance are labeled “+” (n = 3). Tile colour indicates relative mediator concentration: red, increased; green, decreased; black, at median concentration (for the samples). On the horizontal axis the samples segregated into two main clusters, cluster one and two, corresponding significantly to discordant and non-discordant samples respectively (p < 0.0001). Grouped in cluster one were all samples with CSF HIV-1 RNA >1log10 plasma, all with CSF HIV-1 RNA 0.5–1log10 plasma, and two of the three with ultrasensitive discordance. One subject with ultrasensitive discordance (CSF HIV-1 RNA 74, plasma <7 copies/ml) was grouped in cluster two. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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