Hepatitis C virus core protein induces neuroimmune activation and potentiates human immunodeficiency virus-1 neurotoxicity

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<sec> <title>Background</title> <p>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.</p> </sec><sec> <title>Methodology</title> <p>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.</p> </sec><sec> <title>Principal Findings</title> <p>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-1+�, interleukin-6 and tumor necrosis factor-+� in microglia (<italic>p</italic>&lt;0.05) but not in astrocytes while increased chemokine (e.g. CXCL10 and interleukin-8) expression was observed in both microglia and astrocytes (<italic>p</italic>&lt;0.05). HCV core protein modulated neuronal membrane currents and reduced both +�-III-tubulin and lipidated LC3-II expression (<italic>p</italic>&lt;0.05). Neurons exposed to supernatants from HCV core-activated microglia exhibited reduced +�-III-tubulin expression (<italic>p</italic>&lt;0.05). HCV core protein neurotoxicity and interleukin-6 induction were potentiated by HIV-1 Vpr protein (<italic>p</italic>&lt;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 (<italic>p</italic>&lt;0.05).</p> </sec><sec> <title>Conclusions</title> <p>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.</p> </sec>




Vivithanaporn, P., Maingat, F., Lin, L. T., Na, H., Richardson, C. D., Agrawal, B., … Power, C. (2010). Hepatitis C virus core protein induces neuroimmune activation and potentiates human immunodeficiency virus-1 neurotoxicity. PLoS ONE, 5(9), 1–14. https://doi.org/10.1371/journal.pone.0012856

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