How HCV ‘Ghosts’ the Immune System

Scientists from Trinity College Dublin have discovered how the highly infectious and sometimes deadly Hepatitis C virus (HCV) ‘ghosts’ our immune system and remains undiagnosed in many people. The findings were published yesterday in the FASEB journal.

HCV’s main route of transmission is via infected blood, but over the past 40 years, it has been given accidentally to many patients across the world via infected blood products. The virus replicates particularly well in the liver, and the damage it causes makes it a leading cause of liver disease worldwide.

Even though HCV can be deadly, initial infection is rarely accompanied by any obvious clinical symptoms—for reasons that have, until now, remained unknown. As a result, it often goes undiagnosed for the first 6–12 months following infection.

If left untreated, HCV spreads throughout the liver, stimulating a low-level inflammatory response. Over several months, these mild responses—accompanied by subsequent liver repair—result in fibrotic scarring of the liver. If patients do not realize they are infected with HCV, their first noticeable symptoms are the side effects of liver fibrosis, such as jaundice.

While the majority of HCV infections are now treatable with new medicines, early detection would avoid the damaging progression to liver disease. Therefore, the researchers set out to understand how the virus avoids being discovered for months after infection.

Under normal circumstances, our cells communicate with each other using molecules called cytokines, which work by activating signaling cascades within a cell. Cytokines trigger the expression of hundreds of molecules to increase inflammation and anti-viral activity. Uncontrolled inflammation is dangerous, however, so to ensure that the immune response is appropriately regulated, several cytokine signaling pathways are controlled by immune regulators called ‘Suppressor Of Cytokine Signaling (SOCS)’ regulators. After a period of time following an initial response, pro-inflammatory cytokine signaling pathways are shut down by SOCS.

“We’ve discovered that HCV hijacks this regulatory process by causing the expression of SOCS in our cells,” says senior author Nigel Stevenson. “By increasing the expression of SOCS, HCV basically dulls the normal immune response to viral infection. Without a strong signal, our body’s cells cannot then mount an effective inflammatory and anti-viral response that clears infection.”

Image: The HCV p7 protein in the cell's endoplasmic reticulum membrane. Trinity Researchers have discovered that the HCV-p7 protein stimulates the expression of SOCS, which then suppresses normal inflammation. Image courtesy of Nexu Science Communication.