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New research into HepC with wide implications |
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Technophobe
Assistant Admin Joined: January 16 2014 Location: Scotland Status: Offline Points: 88450 |
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Posted: May 23 2014 at 3:25am |
Recent functional genomics studies including genome-wide small
interfering RNA (siRNA) screens demonstrated that hepatitis C virus
(HCV) exploits an extensive network of host factors for productive
infection and propagation. How these co-opted host functions interact
with various steps of HCV replication cycle and exert pro- or antiviral
effects on HCV infection remains largely undefined. Here we present an
unbiased and systematic strategy to functionally interrogate HCV host
dependencies uncovered from our previous infectious HCV (HCVcc) siRNA
screen. Applying functional genomics approaches and various in vitro
HCV model systems, including HCV pseudoparticles (HCVpp), single-cycle
infectious particles (HCVsc), subgenomic replicons, and HCV cell culture
systems (HCVcc), we identified and characterized novel host factors or
pathways required for each individual step of the HCV replication cycle.
Particularly, we uncovered multiple HCV entry factors, including
E-cadherin, choline kinase α, NADPH oxidase CYBA, Rho GTPase RAC1 and
SMAD family member 6. We also demonstrated that guanine nucleotide
binding protein GNB2L1, E2 ubiquitin-conjugating enzyme UBE2J1, and 39
other host factors are required for HCV RNA replication, while the
deubiquitinating enzyme USP11 and multiple other cellular genes are
specifically involved in HCV IRES-mediated translation. Families of
antiviral factors that target HCV replication or translation were also
identified. In addition, various virologic assays validated that 66 host
factors are involved in HCV assembly or secretion. These genes included
insulin-degrading enzyme (IDE), a proviral factor, and N-Myc down
regulated Gene 1 (NDRG1), an antiviral factor. Bioinformatics
meta-analyses of our results integrated with literature mining of
previously published HCV host factors allows the construction of an
extensive roadmap of cellular networks and pathways involved in the
complete HCV replication cycle. This comprehensive study of HCV host
dependencies yields novel insights into viral infection, pathogenesis
and potential therapeutic targets.
Source and full article: http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004163 |
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