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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
A functional genomic screen reveals novel host genes that mediate interferon-alpha's effects against hepatitis C virus
Journal of Hepatology, Volume 56, No. 2, Year 2012
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Description
Background & Aims: The precise mechanisms by which IFN exerts its antiviral effect against HCV have not yet been elucidated. We sought to identify host genes that mediate the antiviral effect of IFN-α by conducting a whole-genome siRNA library screen. Methods: High throughput screening was performed using an HCV genotype 1b replicon, pRep-Feo. Those pools with replicate robust Z scores ≥2.0 entered secondary validation in full-length OR6 replicon cells. Huh7.5.1 cells infected with JFH1 were then used to validate the rescue efficacy of selected genes for HCV replication under IFN-α treatment. Results: We identified and confirmed 93 human genes involved in the IFN-α anti-HCV effect using a whole-genome siRNA library. Gene ontology analysis revealed that mRNA processing (23 genes, p = 2.756e-22), translation initiation (nine genes, p = 2.42e-6), and IFN signaling (five genes, p = 1.00e-3) were the most enriched functional groups. Nine genes were components of U4/U6.U5 tri-snRNP. We confirmed that silencing squamous cell carcinoma antigen recognized by T cells (SART1), a specific factor of tri-snRNP, abrogates IFN-α's suppressive effects against HCV in both replicon cells and JFH1 infectious cells. We further found that SART1 was not IFN-α inducible, and its anti-HCV effector in the JFH1 infectious model was through regulation of interferon stimulated genes (ISGs) with or without IFN-α. Conclusions: We identified 93 genes that mediate the anti-HCV effect of IFN-α through genome-wide siRNA screening; 23 and nine genes were involved in mRNA processing and translation initiation, respectively. These findings reveal an unexpected role for mRNA processing in generation of the antiviral state, and suggest a new avenue for therapeutic development in HCV. © 2011 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.
Authors & Co-Authors
Fusco, Dahlene N.
United States, Boston
Massachusetts General Hospital
Hofmann, Oliver M.
United States, Boston
Harvard T.h. Chan School of Public Health
Jilg, Nikolaus
United States, Boston
Massachusetts General Hospital
Hide, Winston A.
United States, Boston
Harvard T.h. Chan School of Public Health
Chung, Raymond T.
United States, Boston
Massachusetts General Hospital
Statistics
Citations: 55
Authors: 5
Affiliations: 4
Identifiers
Doi:
10.1016/j.jhep.2011.07.026
ISSN:
01688278
Research Areas
Cancer
Genetics And Genomics
Infectious Diseases