A Japanese study led by researchers at Osaka University has discovered a previously unknown molecular mechanism by which the hepatitis C virus (HCV) interacts with the human immune system to cause chronic liver infection.

Reported in the May 24, 2021, online issue of Proceedings of the National Academy of Sciences (PNAS), the study findings may lead to the development of new therapies against chronic HCV infection.

In approximately 75% of patients, HCV results in chronic liver infection, which can cause irreversible liver damage and liver cancer. How the HCV virus evades the immune system to chronically infect the host remains poorly understood.

Although antiviral therapies are available, the development of advanced liver disease and liver cancer is not prevented by this therapeutic approach.

"Currently available HCV antivirals can eliminate HCV from nearly 100% of patients, but liver damage still results in chronically infected patients, despite HCV elimination," noted study co-leader Toru Okamoto.

However, "it remains unclear whether factors other than HCV infection are involved in this liver damage," said the professor in the Institute for Advanced Co-Creation Studies and Research Institute for Microbial Diseases at Osaka University.

Therefore, it is important to understand how HCV manages to evade host immunity to become chronically established, to help develop improved HCV therapies.

In HCV-infected cells, HCV produces various proteins, the stable function of one of which, HCV core protein, is known to require the activity of the host cell's signal peptide peptidase (SPP).

Blocking SPP is known to result in the breakdown of HCV core protein, suppressing infectious HCV particle production, but how the HCV core protein affects the host's immune system has remained unclear.

In their new PNAS study, researchers led by Okamoto and his Osaka University colleague, professor Yoshiharu Matsuura, investigated the connection between SPP and MHC class I proteins in HCV infection.

"MHC class I is known to be a substrate of SPP, but the effects of HCV core protein on the interaction between SPP and MHC class I proteins had not been investigated," said Okamoto, explaining the study's rationale.

In particular, the researchers looked at viral proteins known as immunoevasins, which exist in a number of viruses, including HCV, that prevent antigen presentation on MHC class I proteins, thereby evading host immune recognition.

"When we observed the degradation of MHC class I in SPP knockout (KO) cells, we were confident that HCV core protein could be a newly identified immunoevasin," Okamoto told BioWorld Science.

The researchers then investigated the effects of HCV core protein expression on the stability of MHC class I and found that HCV core protein-induced degradation of MHC class I was mediated through interaction with SPP.

"Our data showed that HCV-infected patients had significantly impaired expression of MHC class I [proteins], and that elimination of HCV led to restoration of that expression," said Okamoto.

"Although this suggests that the liver might recover immune responses related to MHC class I protein expression, this awaits confirmation using a functional assay," he added.

Interestingly, in the presence of HCV core protein, SPP was shown to be unable to interact properly with MHC class I proteins, which were then degraded via HMG-CoA reductase degradation 1 homolog (HRD1).

Consequently, cellular presentation of viral particles to immune cells was found to be impaired, with continuing HCV infection.

To explore whether this might be a common mechanism to evade host immunity in other viral infections, the researchers looked at human cytomegalovirus (HCMV), which is known to damage the liver and other organs.

This showed that a protein produced by HCMV, US2 protein, was structurally similar to HCV core protein and induced degradation of MHC class I proteins by targeting SPP.

"Our findings suggest that HCV core protein and HCMV US2 may have independently evolved to target SPP, suggesting that SPP might be a suitable target for the downregulation of MHC class I proteins," said Okamoto.

"HCV and HCMV may therefore cause chronic infection by targeting SPP to achieve immune evasion."

These findings are in accordance with previous work at Osaka University, which showed that SPP inhibitors could suppress HCV propagation and pathogenesis, both in vitro and in vivo.

"However, that research involved the use of a gamma secretase inhibitor, so we need to develop SPP-specific inhibitors," Okamoto said.

In future he said, "we believe that HCV needs SPP not only for viral production and immune regulation, but also for other functions. Thus, we intend to investigate SPP further, in order to understand more comprehensively SPP's role in the HCV life cycle and liver disease progression."