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HCV Core Protein Induces Neuroinflammation and Potentiates HIV Vpr Neurotoxicity
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Reported by Jules Levin
CROI 2010 Feb 16-19 SF
Pornpun Vivithanaporn*1,2, F Maingat1, B Agrawal1, E Cohen3, and C Power1
1Univ of Alberta, Edmonton, Canada; 2Faculty of Sci, Mahidol Univ, Bangkok, Thailand; and 3Univ of Montreal, Canada
Background: Hepatitis C virus (HCV) genomes and proteins are detected in post-mortem brains indicating productive infection of the central nervous system. The impact of HIV/HCV co-infection on neuropathogenesis remains unclear. Here we hypothesize that HCV co-infection amplifies HIV neuropathogenesis, through mechanisms mediated directly by viral proteins.
Methods: HCV RNA in human brain tissue as well as host immune gene transcripts in human fetal microglia and astrocytes following HCV Core protein exposure were measured by real time RT-PCR. Human fetal neurons were exposed to HCV Core protein with and without concurrent HIV Vpr exposure or supernatants from Core-treated human glia. Cell viability was measured by beta-tubulin immunoreactivity and expression of the autophagy-related molecule LC3 was determined by immunoblotting. Neurobehavioral performance of Vpr-transgenic mice receiving intrastriatal stereotactic implants of HCV Core was measured and corresponding brain sections were stained with cresyl violet and anti-Iba-1 to detect neurons and microglia, respectively.
Results: Positive-strand HCV RNA was detectable in white matter, cortex, and basal ganglia at 102 copies/mg RNA, which was 10-fold lower than in spleen. In contrast, negative-strand RNA, an indicative of viral replication, was found only in white matter and basal ganglia. Exposure of HCV Core protein induced expression of pro-inflammatory cytokines, including interleukin-1b, interleukin-6 and tumor necrosis factor alpha (TNF-α) in microglia, but not in astrocytes while increased chemokine (e.g. CXCL10 and interleukin-8) expression was observed in both microglia and astrocytes. Direct exposure of HCV Core protein to human neurons reduced beta-tubulin and lipidated LC3-II expression. The neurotoxicity of HCV core protein was potentiated by the presence of Vpr protein at subtoxic concentrations. Vpr transgenic mice receiving implants of HCV Core protein showed higher ipsiversive rotary behavior at day 7 and 14 post implantation. HCV Core-exposed mice displayed lower neuronal counts together with higher Iba-1 immunoreactivity.
Conclusions: HCV infection in brain induces inflammation and neuronal injury through both direct and indirect implantation. The in vitro and in vivo additive neurotoxic effects of HCV- and HIV-encoded proteins underscore the adverse impacts of HCV infection on the HIV disease course.
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