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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-\u03baB 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-\u03baB 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 <jats:italic>in vitro<\/jats:italic> studies demonstrate that HCV Env glycoprotein activates host ER Stress Pathways known to inhibit NF-\u03baB activity. This has potential implications for understanding HCV induced immune activation as well as oncogenesis.<\/jats:p>","DOI":"10.3389\/fimmu.2022.831695","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T06:57:04Z","timestamp":1647327424000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["The HCV Envelope Glycoprotein Down-Modulates NF-\u03baB Signalling and Associates With Stimulation of the Host Endoplasmic Reticulum Stress Pathway"],"prefix":"10.3389","volume":"13","author":[{"given":"Lindsay G. 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