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

Pornpun Vivithanaporn, Ferdinand Maingat, Liang Tzung Lin, Hong Na, Christopher D. Richardson, Babita Agrawal, Éric A. Cohen, Jack H. Jhamandas, Christopher Power

Research output: Contribution to journalArticlepeer-review

65 Citations (Scopus)

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.

Original languageEnglish
Article numbere12856
Pages (from-to)1-14
Number of pages14
JournalPLoS ONE
Volume5
Issue number9
DOIs
Publication statusPublished - 2010
Externally publishedYes

ASJC Scopus subject areas

  • General

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