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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/28443
Title: Hepatitis C virus core protein induces neuroimmune activation and potentiates human immunodeficiency virus-1 neurotoxicity
Authors: Pornpun Vivithanaporn
Ferdinand Maingat
Liang Tzung Lin
Hong Na
Christopher D. Richardson
Babita Agrawal
Éric A. Cohen
Jack H. Jhamandas
Christopher Power
University of Alberta
Mahidol University
Dalhousie University
Institut de Recherches Cliniques de Montreal
Keywords: Agricultural and Biological Sciences;Biochemistry, Genetics and Molecular Biology
Issue Date: 29-Oct-2010
Citation: PLoS ONE. Vol.5, No.9 (2010), 1-14
Abstract: Background: Hepatitis C virus (HCV) genomes and proteins are present in human brain tissues although the impact of HIV/ HCV co-infection on neuropathogenesis remains unclear. Herein, we investigate HCV infectivity and effects on neuronal survival and neuroinflammation in conjunction with HIV infection. Methodology: Human microglia, astrocyte and neuron cultures were infected with cell culture-derived HCV or exposed to HCV core protein with or without HIV-1 infection or HIV-1 Viral Protein R (Vpr) exposure. Host immune gene expression and cell viability were measured. Patch-clamp studies of human neurons were performed in the presence or absence of HCV core protein. Neurobehavioral performance and neuropathology were examined in HIV-1 Vpr-transgenic mice in which stereotaxic intrastriatal implants of HCV core protein were performed. Principal Findings: HCV-encoded RNA as well as HCV core and non-structural 3 (NS3) proteins were detectable in human microglia and astrocytes infected with HCV. HCV core protein exposure induced expression of pro-inflammatory cytokines including interleukin-1b, interleukin-6 and tumor necrosis factor-α in microglia (p<0.05) but not in astrocytes while increased chemokine (e.g. CXCL10 and interleukin-8) expression was observed in both microglia and astrocytes (p<0.05). HCV core protein modulated neuronal membrane currents and reduced both β-III-tubulin and lipidated LC3-II expression (p<0.05). Neurons exposed to supernatants from HCV core-activated microglia exhibited reduced b-III-tubulin expression (p<0.05). HCV core protein neurotoxicity and interleukin-6 induction were potentiated by HIV-1 Vpr protein (p<0.05). HIV-1 Vpr transgenic mice implanted with HCV core protein showed gliosis, reduced neuronal counts together with diminished LC3 immunoreactivity. HCV core-implanted animals displayed neurobehavioral deficits at days 7 and 14 post-implantation (p<0.05). Conclusions: HCV core protein exposure caused neuronal injury through suppression of neuronal autophagy in addition to neuroimmune activation. The additive neurotoxic effects of HCV-and HIV-encoded proteins highlight extrahepatic mechanisms by which HCV infection worsens the disease course of HIV infection. © 2010 Vivithanaporn et al.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=77958458743&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/28443
ISSN: 19326203
Appears in Collections:Scopus 2006-2010

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