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Transcript of Www.aids2014.org High Ratios of Circulating Pro-Inflammatory Cytokines to Anti-Inflammatory IL-10...
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High Ratios of Circulating Pro-Inflammatory Cytokines to Anti-Inflammatory IL-10 Correlate with Regional Brain Atrophy in Chronic Suppressed HIV Infection
KJ Kallianpur, M Sakoda, TM Umaki, PJ Norris, SM Keating, JD Barbour, LC Ndhlovu, D Chow, ES Nakasone, CM Shikuma
The authors report no conflicts of interest.
H a w a i ' i C e n t e r f o r A I D SU n i v e r s i t y o f H a w a i ' i - M a n o a
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Background
Cytokine levels increase in HIV infection and predict disease progression, mortality
Inflammatory cytokines may contribute to blood-brain barrier disruption
HIV-associated neurocognitive disorders (HAND)
Brain atrophy, microstructural white matter alterations, subcortical brain injury associated with high plasma MCP-11,2
1Ragin et al, 2006; 2Ragin et al, 2010
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Chronic HIV disease Inflammatory markers (IL-6, IL-8,
TNF-α,…) remain elevated after successful combination antiretroviral therapy (cART)
Plasma cytokines associated with memory performance in HIV1
1Correia et al, 2013
IL-10 inhibits monocyte synthesis of
pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α…)
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Why consider ratios of cytokines to IL-10?
Balance between TNF-α and IL-10 may be important in HIV pathogenesis3
High TNF-α/IL-10 → HIV disease progression4
The balance between pro-inflammatory mediators and anti-inflammatory IL-10 may be important in neurological disease.
1Remarque et al, 2001; 2Dhabhar et al, 2009; 3Fauci et al, 1996; 4Stylianou et al, 1999
Alzheimer’s disease1: IL-1β/IL-10Major depression2 : IL-6/IL-10, low IL-10
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Objectives
i. volumes of brain regions
ii. neuropsychological test performance
To investigate relationships of plasma cytokine levels (concentrations as well as ratios over IL-10) to
in chronic suppressed HIV disease.
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Methods and study participants N=52: HIV+ subjects in HAHC-CVD†
study who underwent neuropsychological (NP) testing and brain magnetic resonance imaging (MRI)
Age ≥ 40 years
On cART for > 6 months prior to entry
Cytokine levels measured by multiplex Luminex assay
Cross-sectional assessment
†HIV Aging with HIV-Cardiovascular Disease
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Abbreviation CytokineIL-1β, IL-6, IL-8, IL-10 Interleukin-1β, etc.
TNF-α Tumor necrosis factor-αMCP-1 Monocyte chemotactic protein-1VEGF Vascular endothelial growth factor IFN-γ Interferon-γ
NT-proBNP N-terminal prohormone of brain natriuretic peptide
sE-Selectin Soluble E-SelectinsVCAM-1 Soluble vascular cell adhesion molecule-1
sICAM-1 Soluble intercellular cell adhesion molecule-1
MMP-9 Matrix metallopeptidase-9MPO Myeloperoxidase tPAI-1 Tissue plasminogen activator inhibitor-1 CRP C-reactive proteinSAA Serum amyloid ASAP Serum amyloid P
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T1-weighted MRI at 3.0T (3D turbo field echo sequence); processed with FreeSurfer
Volumes of 10 brain structures, and 3 composite gray and white matter volumes
MRI data acquisition and processing
Regional brain volumes assessedThalamus Corpus callosumCaudate nucleus Cortical gray matterPutamen Cerebral white matterGlobus pallidus Cerebellar gray matterHippocampus Cerebellar white matterAmygdala Total subcortical gray
matterNucleus accumbens
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Global & composite NP z-scoresNP z-score NP domain
NPZ_14 GlobalNPZpm Psychomotor speedNPZlrn_mem Learning and memory NPZef Executive function
NPZwm Working memory
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Data analysis
Multivariate linear regression effects of cytokines (concentrations
and ratios to IL-10) on regional brain volumes
controlled for age, nadir CD4 count, and intracranial volume
Pearson correlation NP z-scores and cytokine levels
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Variable Mean ± SD, or n (%)N 52Age (years) 50.8 ± 7.1 (40.0 – 70.0)Sex (% male) 44 (85%) Education (years) 14.4 ± 2.3 (8 – 19)Undetectable plasma HIV RNA (< 50 copies/mL) 43 (88%)
Current CD4 count (cells/mm3)465.9 ± 213.2 (33.0 – 955.0)
Nadir CD4 cell count (cells/mm3) 154.5 ± 132.8 (0 – 550.0) Ethnicity (Caucasian) 28 (54%)NPZ_14 [global] -0.07 ± 0.56NPZpm [psychomotor speed] 0.28 ± 0.62NPZlrn_mem [learning & memory] -0.26 ± 1.03NPZef [executive function] 0.15 ± 0.99NPZwm [working memory] -0.14 ± 0.78
Results: Patient characteristics
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Brain region (volume, mm3)
Cytokine [ ] (pg/mL) p β
Adjusted R2 (model)
Globus pallidus IL-1β 0.0016 -0.40 0.41
Putamen IL-1β 0.0035 -0.36 0.43
Cerebral white matter
IL-8 0.0036 -0.30 0.60tPAI-1 0.0345 -0.23 0.56sE_Selectin 0.0345 -0.22 0.56
Cortical gray matter tPAI-1 0.0446 -0.23 0.50
Nucleus accumbens
SAP 0.0276 -0.31 0.27MPO 0.0446 -0.28 0.25
Cytokine concentrations and regional volumes
No volume-cytokine associations with p < 0.001
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Region (mm3)
Cytokine ratio p β Adjusted R2 (model)
White matter (cerebral)
MPO/IL-10 0.0006 -0.36 0.64IL-1β/IL-10 0.0008 -0.36 0.63sE-Selectin/IL-10 0.0009 -0.34 0.63IL-8/IL-10 0.0012 -0.34 0.62VEGF/IL-10 0.0013 -0.34 0.62TNF-α/IL-10 0.0018 -0.33 0.62NT_ProBNP/IL-10 0.0052 -0.30 0.60IL-6/IL-10 0.0053 -0.29 0.60MCP-1/IL-10 0.0070 -0.29 0.59MMP-9/IL-10 0.0113 -0.28 0.58
Cytokine ratios and volumes: white matter
In bold: p < 0.001
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Region (mm3) Cytokine ratio p β Adjusted
R2 (model)
Thalamus
MPO/IL-10 0.0047 -0.36 0.45IL-1β/IL-10 0.0048 -0.38 0.45VEGF/IL-10 0.0056 -0.35 0.44 TNF-α/IL-10 0.0061 -0.34 0.44MCP-1/IL-10 0.0097 -0.33 0.43sE-Selectin/IL-10 0.0136 -0.31 0.42IL-8/IL-10 0.0181 -0.30 0.41MMP-9/IL-10 0.0114 -0.32 0.43 IFN-γ/IL-10 0.0381 -0.27 0.39
Cytokine ratios and volumes: thalamus
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Cytokine concentrations correlated inversely with composite NP z-scores
i.Executive function
ii.Psychomotor speed
iii.Learning and memory MCP-1 and NPZlrn_mem: β = -0.37, p=0.02
SAP and NPZef: β = -0.45, p=0.002 MPO and NPZef: β = -0.34, p=0.03
VEGF and NPZpm: β = -0.41, p=0.007 IL-6 and NPZpm: β = -0.31, p=0.043
Global and composite NP z-scores did not relate to cytokine ratios
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Summary
High ratios of multiple pro-inflammatory circulating cytokines to IL-10 decreased white matter, thalamus
volume
Most absolute cytokine concentrations did not relate to regional brain volumes (though IL-1β, IL-8 showed volumetric associations with p<0.01)
Elevated cytokine concentrations (not ratios) neurocognitive impairment
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Study limitations
Cross-sectional
No HIV-negative controls
Relatively small N
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Conclusions
High circulating cytokine ratios to IL-10 (particularly with co-occurrence of elevated IL-1β or IL-8) may mark brain atrophy in HIV patients on cART
An inflammatory environment characterized by inadequate IL-10 response to elevated pro-inflammatory cytokines may be a key factor in HIV neuropathogenesis and persistence of HAND.
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Additional points
i. IL-1β/IL-10, etc. may reflect the immune status of chronically HIV-infected patients
ii. Pro- to anti-inflammatory cytokine ratios should be studied further as potential markers of disease severity that can supplement traditional assessment
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Grant support: NIH grants R01HL095135, U54RR026136, U54MD007584
Acknowledgments: Sincere thanks to our patients and staff for making this study possible.
Thank you
John A. Burns School of Medicine, University of Hawai’i at Manoa
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Points for discussion
a) Why do multiple cytokine ratios over IL-10 correlate with regional brain volumes but not with NP scores?
b) Any other anti-inflammatory cytokines that should be examined (in pro- to anti-inflammatory ratios)?
c) Can circulating cytokine ratios be used early in disease to identify patients at higher risk of brain atrophy or neurocognitive problems?