How the hepatitis C virus eludes the immune system


We have shown how HCV and HCV prevent antigen presentation in MHC class I molecules. Expression of HCV nucleus protein or HCV U2 protein inhibited SPP and subsequently induced degradation of MHC class I molecules. We also discovered a deterioration of MHC class I molecules in CoreTg mice and HCV-infected patients. We found that the HCV nucleus protein interfered with the interaction of SPP with HLA-A, thus inducing the accumulation of immature HLA and subsequent HRD1-dependent degradation by proteasomes. Credit: Osaka University

Hepatitis C virus (HCV) can cause chronic liver infection, which can lead to irreversible liver damage and liver cancer. It is not entirely understood how HCV manages to bypass the immune system to infect the host chronically. In a new study, researchers at Osaka University discovered a new molecular mechanism by which HCV interferes with the host’s immune system to cause a chronic liver infection. These results may help establish a new therapy for chronic HCV infection.

HCV infection becomes chronic in approximately 80% of patients. There are antiviral therapies that can improve patients ’conditions, but liver disease and, consequently, the formation of liver cancer is not sufficiently mitigated by this therapeutic approach. Therefore, it is important to understand how HCV manages to elude the host’s immune system in the first place to establish itself chronically, to help researchers develop new and better therapies against the disease.

At the molecular level, HCV produces a single protein in infected cells that then divides into ten individual proteins. One of these proteins is the HCV nucleus protein, which for stable function requires the action of one of the host cell proteins, the signal peptidase (SPP) peptide. Researchers know that blocking SPP causes the breakdown of the HCV nucleus protein and therefore suppresses the production of HCV infectious particles. However, the ways in which the basic protein affects the host’s immune system have not been clear so far.

“Immunoevasins, which are proteins that help viruses bypass the host’s immune system, exist in several viruses, such as Epstein-Barr virus, ebolavirus, cytomegalovirus, and hepatitis C virus,” he says. the first author of the Junki Hirano study. “When cells are infected with a virus, they degrade and loading the fragments into so-called MHC class I proteins, so that specific immune cells can detect the ongoing viral infection from outside the infected cells and eliminate them. In this study, we wanted to understand the connection between the signal peptidase peptide and MHC class I proteins in the context of hepatitis C infection. “

To achieve their goal, the researchers first employed a human liver cell line to understand how HCV nuclear proteins, SPP and MHC class I proteins interact. They found that SPP is required for the production of molecules. MHC class I to allow an adequate immune response to liver cells. However, in the presence of the HCV nucleus protein, SPP cannot properly interact with MHC class I proteins, which are then degraded by the actions of another protein, the degradation homologue of the HCV. HMG-CoA reductase 1 (HRD1). As a result, the cellular presentation of viral particles in immune cells is affected and the infection continues to be chronic.

The researchers then asked if this could be a common mechanism to bypass the host’s immune system in other virus infections. They were addressed to human cytomegalovirus (HCMV), a known to damage the in addition to other organs, such as the eyes and esophagus. They found that a protein produced by HCMV, the US2 protein, is structurally similar to the HCV nucleus. and similarly induces degradation of MHC class I proteins by targeting SPP.

“These are surprising results that show how HCV and HCV can cause chronic infections by targeting the signal peptidase to achieve immune evasion,” says study lead author Professor Toru Okamoto. “Our study revealed a novel whereby these viruses target an important component of the human being , MHC class I molecules, to interfere with the proper immune response. These findings could help with the development of new therapies against persistence caused by these viruses “.

The virus co-opts the immune protein to prevent antiviral defenses

More information:
Junki Hirano et al., “Hepatitis C virus modulates peptidase signaling signal to alter host protein processing.” PNAS (2021).

Citation: How the hepatitis C virus eludes the immune system (2021, May 24) recovered on May 25, 2021 at html

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