Hepatitis C is a silent yet formidable liver infection caused by the hepatitis C virus (HCV). Unlike its acute form, which often resolves on its own, chronic hepatitis C persists, potentially leading to severe liver damage, including cirrhosis and cancer. While groundbreaking advancements in direct-acting antiviral (DAA) treatments have revolutionized HCV management, achieving high cure rates, the battle isn’t entirely won. Emerging research indicates that the virus leaves a lasting imprint on the immune system, even after successful treatment.
In a study published in the Journal of Hepatology, researchers from the Institute for Basic Science (IBS) Korea Virus Research Institute (KVRI) found that, during chronic HCV infection, regulatory T cells (Tregs) expand and take on inflammatory traits. These traits persist even after the virus is cleared due to lasting epigenetic marks or “scars.” As a result, Tregs continue to display ongoing inflammatory properties.
Epigenetic marks, like DNA methylation and histone modifications, are chemical alterations to DNA or the histone proteins around which DNA is wrapped. They are crucial for regulating gene expression without altering the DNA sequence. Epigenetic scars are persistent modifications that remain even after the original cause is removed, leading to lasting changes in gene expression and cellular behavior.
In previous posts, we explored how certain health events, such as a heart attack or binge drinking, can leave long-lasting epigenetic marks that negatively affect health. In this study, Director Shin Eui-Cheol and his team from IBS-KVRI’s Center for Viral Immunology investigated the enduring health effects of chronic HCV infection.
The researchers examined patients with chronic HCV infection who achieved a sustained virologic response (SVR) after DAA treatment—the absence of detectable HCV in the blood, indicating successful eradication of the virus. They found that the frequency of activated Treg cells remained elevated throughout the treatment and continued to be high even after the virus was cleared.
Following these initial findings, a comprehensive analysis using RNA sequencing and ATAC-seq was conducted. This analysis showed that even after the virus was eradicated, the transcriptomic and epigenetic profiles of Treg cells in HCV patients remained altered. Key inflammatory features, such as increased TNF signaling, persisted in these Treg cells, suggesting long-term immune system changes due to chronic infection. These activated Treg cells continued to produce inflammatory cytokines like TNF, IFN-γ, and IL-17A well after the virus was cleared. The researchers monitored patients for up to six years post-SVR, confirming the persistence of these inflammatory characteristics.
“Our findings highlight the need for ongoing monitoring even after HCV has been cleared,” explained Director Shin. “By understanding the underlying mechanisms of these persistent immune changes, we can develop more effective strategies to ensure complete recovery and improve the quality of life for HCV patients.”
The implications of this study are important for the future care of patients who have been treated for chronic HCV infection. Although the virus is successfully cleared, the continued presence of inflammatory traits in Treg cells suggests a risk for long-term immune system dysregulation. This may lead to chronic inflammation and related health concerns.
The research team is now focusing on further investigating the mechanisms behind the sustained inflammatory state of Treg cells. They aim to explore potential therapeutic interventions that could reverse these epigenetic and transcriptomic changes.
“We are now interested in seeing whether other chronic viral infections also cause long-lasting epigenetic changes in our immune systems,” said Director Shin. “One of our goals is to identify clinical implications of these persistent immune alterations.”
As more research is needed, the team’s next step is to focus on how these epigenetic changes persist and contribute to ongoing inflammation. Potential therapeutic targets to reverse these alterations are also being explored.
Source: Kim SY, Koh JY, Lee DH, et al. Epigenetic scars in regulatory T cells are retained after successful treatment of chronic hepatitis C with direct-acting antivirals. J Hepatol. June 13, 2024.
Resource: Institute for Basic Science. Hepatitis C Leaves “Scars” in Immune Cells Even After Successful Treatment. July 9, 2024.
