EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy

被引：567

作者：

Lupberger, Joachim ^{[1
,2
]}

Zeisel, Mirjam B. ^{[1
,2
]}

Xiao, Fei ^{[1
,2
]}

Thumann, Christine ^{[1
,2
]}

Fofana, Isabel ^{[1
,2
]}

Zona, Laetitia ^{[1
,2
]}

Davis, Christopher ^{[3
]}

Mee, Christopher J. ^{[3
]}

Turek, Marine ^{[1
,2
]}

Gorke, Sebastian ^{[4
]}

Royer, Cathy ^{[1
,2
]}

Fischer, Benoit ^{[5
]}

Zahid, Muhammad N. ^{[1
,2
]}

Lavillette, Dimitri ^{[6
]}

Fresquet, Judith ^{[6
]}

Cosset, Francois-Loic ^{[6
]}

Rothenberg, S. Michael ^{[7
,8
]}

Pietschmann, Thomas ^{[9
]}

Patel, Arvind H. ^{[10
]}

Pessaux, Patrick ^{[11
]}

Doffoel, Michel ^{[11
]}

Raffelsberger, Wolfgang ^{[5
]}

Poch, Olivier ^{[5
]}

McKeating, Jane A. ^{[3
]}

Brino, Laurent ^{[5
]}

Baumert, Thomas F. ^{[1
,2
,5
,11
]}

机构：

[1] INSERM, U748, Strasbourg, France

[2] Univ Strasbourg, Strasbourg, France

[3] Univ Birmingham, Div Immun & Infect, Hepatitis C Res Grp, Birmingham, W Midlands, England

[4] Univ Freiburg, Dept Med 2, Freiburg, Germany

[5] Univ Strasbourg, INSERM, CNRS, Inst Genet & Biol Mol & Cellulaire,U964,UMR1704, Illkirch Graffenstaden, France

[6] Univ Lyon 1, INSERM, Ecole Normale Super, Inst Fed Rech 128,U758, F-69365 Lyon, France

[7] Massachusetts Gen Hosp, Ctr Canc, Howard Hughes Med Inst, Charlestown, MA USA

[8] Harvard Univ, Sch Med, Charlestown, MA USA

[9] Ctr Expt & Clin Infect Res, TWINCORE, Div Expt Virol, Hannover, Germany

[10] Univ Glasgow, MRC, Ctr Virus Res, Glasgow, Lanark, Scotland

[11] Hop Univ Strasbourg, Strasbourg, France

来源：

NATURE MEDICINE | 2011年 / 17卷 / 05期

基金：

英国医学研究理事会; 英国惠康基金; 欧洲研究理事会;

关键词：

EPIDERMAL-GROWTH-FACTOR; B TYPE-I; FACTOR RECEPTOR; NEUTRALIZING ANTIBODIES; CELL TRANSMISSION; HUMAN LIVER; INFECTION; ACTIVATION; ERLOTINIB; MOUSE;

D O I：

10.1038/nm.2341

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Hepatitis C virus (HCV) is a major cause of liver disease, but therapeutic options are limited and there are no prevention strategies. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screen, we identified epidermal growth factor receptor and ephrin receptor A2 as host cofactors for HCV entry. Blocking receptor kinase activity by approved inhibitors broadly impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model in vivo. The identified receptor tyrosine kinases (RTKs) mediate HCV entry by regulating CD81-claudin-1 co-receptor associations and viral glycoprotein-dependent membrane fusion. These results identify RTKs as previously unknown HCV entry cofactors and show that tyrosine kinase inhibitors have substantial antiviral activity. Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection.

引用

页码：589 / U109

页数：8

共 54 条

[1] Viral and cellular determinants of the hepatitis C virus envelope-heparan sulfate interaction [J].