Abstract
BackgroundHIV-1-related inflammation is associated with increased levels of biomarkers of vascular adhesion and endothelial activation, and may increase production of the inflammatory protein angiopoietin-2 (ANG-2), an adverse prognostic biomarker in severe systemic infection. We hypothesized that antiretroviral therapy (ART) initiation would decrease endothelial activation, reducing plasma levels of ANG-2.MethodsAntiretroviral-naïve Kenyan women with advanced HIV infection were followed prospectively. Endothelial activation biomarkers including soluble intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin, and plasma ANG-2 and angiopoietin-1 (ANG-1) were tested in stored plasma samples from 0, 6, and 12 months after ART initiation. We used Wilcoxon matched-pairs signed rank tests to compare endothelial activation biomarkers across time-points, generalized estimating equations to analyze associations with change in log10-transformed biomarkers after ART initiation, and Cox proportional-hazards regression to analyze associations with mortality.ResultsThe 102 HIV-1-seropositive women studied had advanced infection (median CD4 count, 124 cells/μL). Soluble ICAM-1 and plasma ANG-2 levels decreased at both time-points after ART initiation, with concomitant increases in the beneficial protein ANG-1. Higher ANG-2 levels after ART initiation were associated with higher plasma HIV-1 RNA, oral contraceptive pill use, pregnancy, severe malnutrition, and tuberculosis. Baseline ANG-2 levels were higher among five women who died after ART initiation than among women who did not (median 2.85 ng/mL [inter-quartile range (IQR) 2.47–5.74 ng/mL] versus median 1.32 ng/mL [IQR 0.35–2.18 ng/mL], p = 0.01). Both soluble ICAM-1 and plasma ANG-2 levels predicted mortality after ART initiation.ConclusionsBiomarkers of endothelial activation decreased after ART initiation in women with advanced HIV-1 infection. Changes in plasma ANG-2 were associated with HIV-1 RNA levels over 12 months of follow-up. Soluble ICAM-1 and plasma ANG-2 levels represent potential biomarkers for adverse outcomes in advanced HIV-1 infection.
Highlights
HIV-1-related inflammation is associated with increased levels of biomarkers of vascular adhesion and endothelial activation, and may increase production of the inflammatory protein angiopoietin-2 (ANG-2), an adverse prognostic biomarker in severe systemic infection
We examined levels of soluble intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin to confirm that changes in these biomarkers accompanied changes in ANG-1 and ANG-2
Plasma concentrations of ANG-1 (1:5), ANG-2 (1:5), soluble ICAM-1 (1:1000), soluble VCAM-1 (1:2000), and soluble E-selectin (1:50) were measured by ELISA (R&D Systems Duoset kits, Minneapolis MN, USA) according to manufacturers’ instructions with modifications: (1) assays were performed in 50 μL per well; (2) plasma samples were incubated overnight at 4°C; and (3) ELISAs were developed using Extravidin®-Alkaline Phosphatase (Sigma-Aldrich Canada Ltd, Oakville, ON, Canada; 1:1000 dilution, 45-minute incubation) followed by addition of p-nitrophenyl phosphate substrate (Sigma-Aldrich Canada Ltd, Oakville, ON, Canada) before optical density reading at 405 nm
Summary
HIV-1-related inflammation is associated with increased levels of biomarkers of vascular adhesion and endothelial activation, and may increase production of the inflammatory protein angiopoietin-2 (ANG-2), an adverse prognostic biomarker in severe systemic infection. We hypothesized that antiretroviral therapy (ART) initiation would decrease endothelial activation, reducing plasma levels of ANG-2. Because even prolonged effective antiretroviral therapy (ART) may not normalize biomarkers of inflammation and coagulation [2], a better understanding of the relationship between inflammatory pathways and HIV-1 pathogenesis is needed. HIV-1-induced inflammation has been linked to increased biomarkers of endothelial activation, including soluble intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin [5,8,9]. Higher levels of soluble ICAM-1 have been associated with increased mortality in HIV-1-infected persons [12]. We hypothesized that the extent of HIV-1-related endothelial activation may be associated with altered levels of the vascular growth factors angiopoietin-1 and-2 (ANG-1 and ANG-2), recently identified as important regulators of endothelial quiescence and activation
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