Pornpun VivithanapornFerdinand MaingatLiang Tzung LinHong NaChristopher D. RichardsonBabita AgrawalÉric A. CohenJack H. JhamandasChristopher PowerUniversity of AlbertaMahidol UniversityDalhousie UniversityInstitut de Recherches Cliniques de Montreal2018-09-242018-09-242010-10-29PLoS ONE. Vol.5, No.9 (2010), 1-14193262032-s2.0-77958458743https://repository.li.mahidol.ac.th/handle/20.500.14594/28443Background: 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.Mahidol UniversityAgricultural and Biological SciencesBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1371/journal.pone.0012856