Krystal Colon1, Juliana Perez-Laspiur2, Raymond Quiles3, Yolanda Rodriguez1, Valerie Wojna4, Scott A Shaffer5, John Leszyk5, Richard L Skolasky6, Loyda M Melendez1,2. 1. Department of Microbiology, Medical Sciences Campus, University of Puerto Rico, San Juan, PR, USA. 2. RCMI Translational Proteomics Center, Medical Sciences Campus, University of Puerto Rico, San Juan, PR, USA. 3. Metropolitan Campus, Interamerican University, San Juan, PR, USA. 4. Division of Neurology, Medical Sciences Campus, University of Puerto Rico, San Juan, PR, USA. 5. Proteomics and Mass Spectrometry Facility, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA. 6. Department of Orthopaedic Surgery, John Hopkins University, Baltimore, MD, USA.
Abstract
PURPOSE: Thirty to 50% of HIV patients develop HIV-associated neurocognitive disorders (HANDs) despite combined antiretroviral therapy. HIV-1-infected macrophages release viral and cellular proteins that induce neuronal degeneration and death. We hypothesize that changes in the macrophage secretome of HIV-1 seropositive patients with HAND may dissect proteins related to neurotoxicity. EXPERIMENTAL DESIGN: Monocyte-derived macrophages (MDMs) were isolated from the peripheral blood of 12 HIV+ and four HIV- women characterized for neurocognitive function. Serum-free MDM supernatants were collected for protein isolation and quantification with iTRAQ® labeling. Protein identification was performed using a LTQ Orbitrap Velos mass spectrometer and validated in MDM supernatants and in plasma using ELISA. RESULTS: Three proteins were different between normal cognition (NC) and asymptomatic neurocognitive disorders (ANI), six between NC and HIV-associated dementia (HAD), and six between NC and HAD. Among these, S100A9 was decreased in plasma from patients with ANI, and metalloproteinase 9 was decreased in the plasma of all HIV+ patients regardless of cognitive status, and was significantly reduced in supernatant of MDM isolated from patients with ANI. CONCLUSIONS AND CLINICAL RELEVANCE: S100A9 and metalloproteinase 9 have been associated with inflammation and cognitive impairment, and therefore represent potential targets for HAND treatment.
PURPOSE: Thirty to 50% of HIV patients develop HIV-associated neurocognitive disorders (HANDs) despite combined antiretroviral therapy. HIV-1-infected macrophages release viral and cellular proteins that induce neuronal degeneration and death. We hypothesize that changes in the macrophage secretome of HIV-1 seropositivepatients with HAND may dissect proteins related to neurotoxicity. EXPERIMENTAL DESIGN: Monocyte-derived macrophages (MDMs) were isolated from the peripheral blood of 12 HIV+ and four HIV- women characterized for neurocognitive function. Serum-free MDM supernatants were collected for protein isolation and quantification with iTRAQ® labeling. Protein identification was performed using a LTQ Orbitrap Velos mass spectrometer and validated in MDM supernatants and in plasma using ELISA. RESULTS: Three proteins were different between normal cognition (NC) and asymptomatic neurocognitive disorders (ANI), six between NC and HIV-associated dementia (HAD), and six between NC and HAD. Among these, S100A9 was decreased in plasma from patients with ANI, and metalloproteinase 9 was decreased in the plasma of all HIV+ patients regardless of cognitive status, and was significantly reduced in supernatant of MDM isolated from patients with ANI. CONCLUSIONS AND CLINICAL RELEVANCE: S100A9 and metalloproteinase 9 have been associated with inflammation and cognitive impairment, and therefore represent potential targets for HAND treatment.
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