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The HCV Envelope Glycoprotein Down-Modulates NF-κB Signalling and Associates With Stimulation of the Host Endoplasmic Reticulum Stress Pathway

McKay, Lindsay G.A.; Thomas, Jordan; Albalawi, Wejdan; Fattaccioli, Antoine; Dieu, Marc; Ruggiero, Alessandra; McKeating, Jane A.; Ball, Jonathan K.; Tarr, Alexander W.; Renard, Patricia; Pollakis, Georgios; Paxton, William A.


Lindsay G.A. McKay

Jordan Thomas

Wejdan Albalawi

Antoine Fattaccioli

Marc Dieu

Alessandra Ruggiero

Jane A. McKeating

Professor of Molecular Virology

Patricia Renard

Georgios Pollakis

William A. Paxton


Following acute HCV infection, the virus establishes a chronic disease in the majority of patients whilst few individuals clear the infection spontaneously. The precise mechanisms that determine chronic HCV infection or spontaneous clearance are not completely understood but are proposed to be driven by host and viral genetic factors as well as HCV encoded immunomodulatory proteins. Using the HIV-1 LTR as a tool to measure NF-κB activity, we identified that the HCV E1E2 glycoproteins and more so the E2 protein down-modulates HIV-1 LTR activation in 293T, TZM-bl and the more physiologically relevant Huh7 liver derived cell line. We demonstrate this effect is specifically mediated through inhibiting NF-κB binding to the LTR and show that this effect was conserved for all HCV genotypes tested. Transcriptomic analysis of 293T cells expressing the HCV glycoproteins identified E1E2 mediated stimulation of the endoplasmic reticulum (ER) stress response pathway and upregulation of stress response genes such as ATF3. Through shRNA mediated inhibition of ATF3, one of the components, we observed that E1E2 mediated inhibitory effects on HIV-1 LTR activity was alleviated. Our in vitro studies demonstrate that HCV Env glycoprotein activates host ER Stress Pathways known to inhibit NF-κB activity. This has potential implications for understanding HCV induced immune activation as well as oncogenesis.


McKay, L. G., Thomas, J., Albalawi, W., Fattaccioli, A., Dieu, M., Ruggiero, A., …Paxton, W. A. (2022). The HCV Envelope Glycoprotein Down-Modulates NF-κB Signalling and Associates With Stimulation of the Host Endoplasmic Reticulum Stress Pathway. Frontiers in Immunology, 13, Article 831695.

Journal Article Type Article
Acceptance Date Feb 21, 2022
Online Publication Date Mar 15, 2022
Publication Date Mar 15, 2022
Deposit Date Nov 9, 2022
Publicly Available Date Nov 9, 2022
Journal Frontiers in Immunology
Electronic ISSN 1664-3224
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 13
Article Number 831695
Keywords Immunology; Immunology and Allergy
Public URL
Publisher URL


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