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

Abstract

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.

SARS-CoV-2 S, M and E Structural Proteins Down-modulate HIV-1 LTR Activity and Modulate Endoplasmic Reticulum Stress Responses

“…Among these pertains to the interplay between SARS-CoV-2 and the host during infection. The findings here demonstrate that SARS CoV-2 S, M and E Env proteins can downmodulate HIV-1 LTR activity, similar to the observed effects of the HCV E1E2 and sE2 Env proteins [34] . Both SARS CoV-2 and HCV are positive-sense RNA viruses that replicate in the cytoplasm and have a similar mechanism of viral assembly and release.…”

“…The medium was then replaced with 50 µl of Opti-MEM. Transfection mixes were prepared by combining 1 ng of Tat plasmid, 6 ng of LTR-luc plasmid, and 12, 6, or 1 ng of SARS-CoV-2 S, M, E and N SARS-CoV-2 variants [34] , or pCDNA plasmid with 2 µl of Opti-MEM. An additional 2 µl of PEI (0.14 μg/μl) was added, and the mix was incubated at room temperature for 30 min.…”