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The authors report no conflicts of interest.

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.

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The authors report no conflicts of interest.

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  1. 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 Hawai'i Center for AIDS University of Hawai'i - Manoa The authors report no conflicts of interest.

  2. 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

  3. 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 • IL-10 • inhibits monocyte synthesis of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α…) 1Correia et al, 2013

  4. Why consider ratios of cytokines to IL-10? The balance between pro-inflammatory mediators and anti-inflammatory IL-10 may be important in neurological disease. Balance between TNF-α and IL-10 may be important in HIV pathogenesis3 High TNF-α/IL-10 → HIV disease progression4 Alzheimer’s disease1: IL-1β/IL-10 Major depression2 : IL-6/IL-10, low IL-10 1Remarque et al, 2001; 2Dhabhar et al, 2009; 3Fauci et al, 1996; 4Stylianou et al, 1999

  5. Objectives To investigate relationships of plasma cytokine levels (concentrations as well as ratios over IL-10) to • volumes of brain regions • neuropsychological test performance in chronic suppressed HIV disease.

  6. 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

  7. MRI data acquisition and processing • 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

  8. 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

  9. Results: Patient characteristics

  10. Cytokine concentrations and regional volumes No volume-cytokine associations with p < 0.001

  11. Cytokine ratios and volumes: white matter In bold: p < 0.001

  12. Cytokine ratios and volumes: thalamus

  13. Cytokine concentrations correlated inversely with composite NP z-scores Executive function Psychomotor speed Learning and memory • 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 • MCP-1 and NPZlrn_mem: β = -0.37, p=0.02 Global and composite NP z-scores did not relate to cytokine ratios

  14. 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

  15. Study limitations • Cross-sectional • No HIV-negative controls • Relatively small N

  16. 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.

  17. Additional points • IL-1β/IL-10, etc. may reflect the immune status of chronically HIV-infected patients • Pro- to anti-inflammatory cytokine ratios should be studied further as potential markers of disease severity that can supplement traditional assessment

  18. Thank you John A. Burns School of Medicine, University of Hawai’i at Manoa Grant support: NIH grants R01HL095135, U54RR026136, U54MD007584 Acknowledgments: Sincere thanks to our patients and staff for making this study possible.

  19. Points for discussion • Why do multiple cytokine ratios over IL-10 correlate with regional brain volumes but not with NP scores? • Any other anti-inflammatory cytokines that should be examined (in pro- to anti-inflammatory ratios)? • Can circulating cytokine ratios be used early in disease to identify patients at higher risk of brain atrophy or neurocognitive problems?

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