Researchers discover how hepatitis C virus leaves a lasting mark on the immune system

It is often said that the only thing you take with you when you're gone is what you leave behind. So, what does a virus leave behind when it's gone?

Surprisingly, little research has been done on the changes that occur after the body recovers from a viral infection.

Researchers, -- from Seoul Metropolitan Government Seoul National University (SMG-SNU) Boramae Medical Center and Severance Hospital at Yonsei University, led by Professor Shin Eui-cheol of KAIST's Graduate School of Medical Sciences and Engineering (GSMSE) and director of the Center of Viral Immunology at the Korea Virus Research Institute (KVRI), launched under the Institute for Basic Science (IBS), -- discovered that the hepatitis C virus (HCV) leaves a lasting mark on patients' immune cells, even after the virus has been eradicated. 

HCV, transmitted through blood or body fluids, often becomes a chronic infection, IBS said. Prolonged inflammation can lead to serious complications, including cirrhosis and liver cancer. While advancements in antiviral drugs have pushed the cure rate close to 100 percent, evidence suggests that patients' immune systems do not fully recover after treatment

To understand these post-treatment changes, IBS researchers focused on regulatory T cells, key players in the regulation and homeostasis of the immune response. During HCV infection, these cells increase in number and undergo significant changes in activity.

The research team collected blood samples from chronic HCV patients and compared the status of regulatory T cells before and after antiviral treatment. They found that the number of regulatory T cells in the peripheral blood remained high even after virus clearance.

RNA-sequencing (RNA-seq) revealed that these cells retained their ability to produce the inflammatory cytokine tumor necrosis factor (TNF), suggesting that the inflammatory properties induced by the viral infection persisted post-cure.

"There have been previous reports that regulatory T cells do not normalize after HCV treatment, but this is the first time we have identified molecular-level changes in cell populations, clearly delineating the 'immune scar' left by the virus," said co-author Kim So-young. 

"While antiviral treatment effectively reduces the risk of complications such as liver cancer, our results show that the immune scars left behind can have long-term effects on the immune system of recovered patients," said co-author Koh June-young.

Koh June-young and Kim So-young are equal contributors to the work and are designated as co-first authors. 

Using an advanced technique called assay for transposase-accessible chromatin with sequencing (ATAC-seq), the researchers analyzed regulatory T cells before and after treatment to investigate acquired changes in gene expression. The results showed that inflammatory epigenetic changes in the immune system persisted even after HCV treatment.

The team speculates that these pro-inflammatory epigenetic changes may predispose patients with chronic HCV to inflammatory diseases even after they are cured. IBS said further clinical studies are needed to better understand the specific impact of regulatory T-cell imprinting on patient health and to improve treatment and management strategies.

"We plan to investigate whether similar epigenetic markers remain in other chronic viral infections," said Professor Shin, who led the study. "It’s possible that long Covid is also caused by markers on regulatory T cells, which requires further study."

The findings were published in the June 13 online edition of the Journal of Hepatology (IF 26.8), an international peer-reviewed medical journal.