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

Lupberger, Joachim; Zeisel, Mirjam B.; Xiao, Fei; Thumann, Christine; Fofana, Isabel; Zona, Laetitia; Davis, Chris; Mee, Christopher; Turek, Marine; Gorke, Sebastian; Royer, Corinne; Fischer, Benoit; Zahid, Muhammad; Lavillette, Dimitri; Fresquet, Judith; Cosset, François‐Loïc; Rothenberg, S. Michael; Pietschmann, Thomas; Patel, Arvind H.; Pessaux, Patrick; Doffoël, Michel; Raffelsberger, Wolfgang; Poch, Olivier; McKeating, Jane A.; Brino, Laurent; Baumert, Thomas F.

doi:10.1038/nm.2341

Cited by 642 publications

(809 citation statements)

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“…To further establish a functional role for receptor tyrosine kinases during KSHV entry, we used dasatinib, a clinically approved tyrosine kinase EphA2 inhibitor (28). Compared with DMSO control, 1 μM and 5 μM dasatinib not only inhibited EphA2 phosphorylation (by 75%) at 10 min p.i.…”

Section: Epha2 Coimmunoprecipitates With Kshv Entry Receptors Early Dmentioning

confidence: 99%

Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

Chakraborty

Veettil

Bottero

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

157

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Kaposi's sarcoma-associated herpesvirus (KSHV), etiologically associated with Kaposi's sarcoma, uses integrins (α3β1, αVβ3, and αVβ5) and associated signaling to enter human dermal microvascular endothelial cells (HMVEC-d), an in vivo target of infection. KSHV infection activated c-Cbl, which induced the selective translocation of KSHV into lipid rafts (LRs) along with the α3β1, αVβ3, and xCT receptors, but not αVβ5. LR-translocated receptors were monoubiquitinated, leading to productive macropinocytic entry, whereas non-LR-associated αVβ5 was polyubiquitinated, leading to clathrin-mediated entry that was targeted to lysosomes. Because the molecule(s) that integrate signal pathways and productive KSHV macropinocytosis were unknown, we immunoprecipitated KSHV-infected LR fractions with anti-α3β1 antibodies and analyzed them by mass spectrometry. The tyrosine kinase EphrinA2 (EphA2), implicated in many cancers, was identified in this analysis. EphA2 was activated by KSHV. EphA2 was also associated with KSHV and integrins (α3β1 and αVβ3) in LRs early during infection. Preincubation of virus with soluble EphA2, knockdown of EphA2 by shRNAs, or pretreatment of cells with anti-EphA2 monoclonal antibodies or tyrosine kinase inhibitor dasatinib significantly reduced KSHV entry and gene expression. EphA2 associates with c-Cbl-myosin IIA and augmented KSHV-induced Src and PI3-K signals in LRs, leading to bleb formation and macropinocytosis of KSHV. EphA2 shRNA ablated macropinocytosis-associated signaling events, virus internalization, and productive nuclear trafficking of KSHV DNA. Taken together, these studies demonstrate that the EphA2 receptor acts as a master assembly regulator of KSHV-induced signal molecules and KSHV entry in endothelial cells and suggest that the EphA2 receptor is an attractive target for controlling KSHV infection.virus entry | productive endocytosis | receptor tyrosine kinase

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Section: Epha2 Coimmunoprecipitates With Kshv Entry Receptors Early Dmentioning

confidence: 99%

Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

Chakraborty

Veettil

Bottero

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

157

View full text Add to dashboard Cite

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“…Monoclonal antibodies directed against viral entry factors (e.g., CD81-mAbs, anti-SR-BI mAbs, ITX5061), or EGFR kinase (erlotinib) and the cholesterol absorption NPC1L1 inhibitor ezetimibe have been shown to protect or delay HCV infection in mice. [65][66][67][68][69][70] As of today, development of these compounds (except ITX5061) is yet in preclinical stages. In a recent phase 1b study ITX5061, however, did not meet protocol-defined criteria for viral suppression.…”

Section: Host-targeting Agentsmentioning

confidence: 99%

Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

Welzel

Zeuzem

2014

Semin Liver Dis

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The establishment of a robust hepatitis C virus (HCV) cell culture system and subsequent detailed characterization of the HCV life cycle was a key step toward the identification of putative antiviral targets and respective antiviral drugs. 1,2 These include direct-acting antiviral agents (DAAs) such as NS3/4A protease inhibitors, NS5A inhibitors, nucleos(t)ide and non-nucleoside polymerase inhibitors, as well as hosttargeting agents (HTAs) directed against cellular factors involved in viral entry or replication. 3 Trials investigating different drug classes with and without pegylated interferon (PegIFN) and/or ribavirin have rapidly evolved, yielding highly promising sustained virologic response (SVR) rates. 4,5 In regard to the enormous public health impact of HCV infection with an estimated 184 million anti-HCV positive persons worldwide, the recent advances in HCV drug development, together with implementation of improved HCV screening programs, have the potential to substantially reduce the burden of HCV-associated advanced liver disease including hepatocellular carcinoma. 6-9The first-in-class NS3/4A inhibitors telaprevir and boceprevir were approved in 2011. Addition of these drugs to the PegIFN/ribavirin backbone has considerably improved response rates in HCV therapy naïve and experienced patients compared with PegIFN/ribavirin alone. [10][11][12][13] The poor side-effect profile of these IFN-based therapies, however, limits the wide clinical applicability. Proof of the principle that viral clearance can be achieved with an IFN-free DAA combination has fast-tracked design and the conduct of clinical trials investigating IFN-free DAA combinations. 14 Different HCV genotypes and multiple subtypes result in a genotype and subtype-dependent efficacy of many available DAAs. 15,16 Furthermore, viral clearance is challenged by the presence and selection of resistance-associated variants (RAVs). 17,18 Thus, essential prerequisites for DAAs in clinical development comprise a high antiviral efficacy, a broad and at best pan-genotypic activity, as well as a high barrier to resistance. In this respect, nucleos(t)ide polymerase inhibitors display very favorable characteristics. [19][20][21] In addition to a high antiviral efficacy, binding to the highly conserved active site of the RNA-dependent RNA-polymerase (RdRp) and incorporation as active triphosphates into the growing HCV RNA chain terminating its elongation, confers a pan-genotypic activity. Also, the low replication fitness of emergent Keywords ► interferon-free HCV treatment ► direct-acting antiviral agents ► NS3/4A protease inhibitors ► NS5A inhibitors ► non-nucleoside polymerase inhibitors ► host-targeting agents AbstractThe identification of viral and host factors involved in hepatitis C virus (HCV) replication was a key prerequisite for the discovery and further exploration of antiviral drug targets. As of today, numerous direct-acting antiviral agents (DAAs), as well as host-targeting agents (HTAs), have been developed and entered clinical testing. The...

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“…De plus, l'EGFR et l'EphA2 jouent un rôle lors de l'étape de fusion membranaire faisant intervenir les glycoprotéines d'enveloppe du VHC. Enfin, ces deux protéines kinases interviennent dans la transmission du virus de cellule à cellule indiquant qu'elles favorisent la dissémination du virus [11]. L'ensemble de ces études suggère que plusieurs protéines kinases interviennent à différentes étapes de l'entrée du VHC dans les hépatocytes et plus particulièrement lors de l'association dans l'entrée du VHC et de préciser le rôle de deux récepteurs à activité tyrosine kinase : le récepteur du facteur de croissance épidermique (EGFR) et l'éphrine A2 (EphA2).…”

Section: Les Inhibiteurs De Protéine Kinases : Vers Une Nouvelle Clasunclassified

“…L'ensemble de ces études suggère que plusieurs protéines kinases interviennent à différentes étapes de l'entrée du VHC dans les hépatocytes et plus particulièrement lors de l'association dans l'entrée du VHC et de préciser le rôle de deux récepteurs à activité tyrosine kinase : le récepteur du facteur de croissance épidermique (EGFR) et l'éphrine A2 (EphA2). Tous deux sont des récepteurs membranaires à activité tyrosine kinase fortement exprimés dans le foie [11]. Ces kinases semblent jouer un rôle au cours de différentes étapes de l'entrée du VHC.…”

Section: Les Inhibiteurs De Protéine Kinases : Vers Une Nouvelle Clasunclassified

“…Le développement de criblages fonctionnels basés sur l'ARN interférence a repré-senté une avancée considérable dans la découverte de nouvelles interactions entre des virus et leurs cellules hôtes [8]. Au cours de ces dernières années, de tels criblages ont été effectués afin de découvrir des facteurs fonctionnels de l'hôte indispensables pour l'entrée du VHC et pouvant constituer de nouvelles cibles pour de futurs antiviraux [10,11]. Ces criblages ont permis d'identifier plusieurs autres protéine kinases impliquées dans l'entrée du VHC.…”

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