A human and rhesus macaque interferon-stimulated gene screen shows that over-expression of ARHGEF3/XPLN inhibits replication of hepatitis C virus and other flavivirids

Bamford, C. G.C., Aranday-Cortes, E. , Sanchez-Velazquez, R., Mullan, C., Kohl, A. , Patel, A. H. , Wilson, S. J. and McLauchlan, J. (2022) A human and rhesus macaque interferon-stimulated gene screen shows that over-expression of ARHGEF3/XPLN inhibits replication of hepatitis C virus and other flavivirids. Viruses, 14(8), 1655. (doi: 10.3390/v14081655)

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Abstract

Natural hepatitis C virus (HCV) infection is restricted to humans, whereas other primates such as rhesus macaques are non-permissive for infection. To identify human and rhesus macaque genes that differ or share the ability to inhibit HCV replication, we conducted a medium-throughput screen of lentivirus-expressed host genes that disrupt replication of HCV subgenomic replicon RNA expressing secreted Gaussia luciferase. A combined total of >800 interferon-stimulated genes (ISGs) were screened. Our findings confirmed established anti-HCV ISGs, such as IRF1, PKR and DDX60. Novel species–specific inhibitors were also identified and independently validated. Using a cell-based system that recapitulates productive HCV infection, we identified that over-expression of the ‘Rho Guanine Nucleotide Exchange Factor 3’ gene (ARHGEF3) from both species inhibits full-length virus replication. Additionally, replication of two mosquito-borne flaviviruses, yellow fever virus (YFV) and Zika virus (ZIKV), were also reduced in cell lines over-expressing ARHGEF3 compared to controls. In conclusion, we ascribe novel antiviral activity to the cellular gene ARHGEF3 that inhibits replication of HCV and other important human viral pathogens belonging to the Flaviviridae, and which is conserved between humans and rhesus macaques.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Wilson, Professor Sam and Mullan, Catrina and Aranday-Cortes, Dr Elihu and Sanchez Velazquez, Ricardo and Bamford, Dr Connor and Patel, Professor Arvind and McLauchlan, Professor John and Kohl, Professor Alain
Authors: Bamford, C. G.C., Aranday-Cortes, E., Sanchez-Velazquez, R., Mullan, C., Kohl, A., Patel, A. H., Wilson, S. J., and McLauchlan, J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:Viruses
Publisher:MDPI
ISSN:1999-4915
ISSN (Online):1999-4915
Published Online:28 July 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Viruses 14(8): 1655
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172630004The factors that drive HCV evolution and development of an antibody-focused prophylactic HCV vaccine (Programme 3)John McLauchlanMedical Research Council (MRC)MC_UU_12014/1III - Centre for Virus Research
172630Basis of the host range and tissue tropism for hepatitis C virusArvind PatelMedical Research Council (MRC)MC_UU_12014/2III - Centre for Virus Research
172630007Arthropod-borne infections and emerging virus infections in high risk areas (Programme 4)Alain KohlMedical Research Council (MRC)MC_UU_12014/8III - Centre for Virus Research
172580The emergence of Zika virus in Brazil: investigating prevalence and host responses to design preventive strategiesAlain KohlMedical Research Council (MRC)MR/N017552/1III-MRC-GU Centre for Virus Research