Researchers Identify Breakthrough In Hepatitis C Virus Infection

Researchers have made a significant advance in the understanding of the hepatitis C virus (HCV) by identifying new genetic factors associated with clearing the virus spontaneously without the necessity for additional treatment. Their findings are set out in a paper published in Science magazine today (6 August 2004).

Hepatitis C virus infects the liver and leads to serious permanent liver damage. The infection affects about 170 million people worldwide and up to 500,000 people in the UK. Most people who come into contact with HCV contract a long-term or chronic infection and, as a consequence, run a significant risk of liver failure – necessitating liver transplantation – or liver cancer.

The new multi-centre study was jointly led by researchers from the University of Southampton’s School of Medicine, the National Genetics Institute, USA, and the Johns Hopkins Hospital, USA. The findings demonstrate that natural killer (NK) cells provide a central defence against HCV infection and that this defence is mediated by specific inhibitory receptors expressed on NK cells and the partners or ligands for these receptors on liver cells.

Over 1,000 patients from the UK and the USA were involved in the study, some of whom were chronically infected and some who had cleared the virus. Researchers identified a specific combination of genes in these individuals that directly confers protection against HCV. The genes are killer cell immunoglobulin-like receptors (KIR) and HLA class I genes and the favourable genes identified in the study are KIR2DL3 and group 1 HLA-C alleles.

Dr Salim Khakoo of Southampton’s Infection, Inflammation and Repair Division, who co-authored the paper with Professor Mary Carrington of the National Genetics Institute in the USA, commented: ’These favourable genes control the functions of NK cells. NK cells are part of the innate immune system, a branch of immunity that has not been well-studied in HCV to date.

’KIR2DL3 on NK cells binds group 1 HLA-C alleles on liver cells and our work suggests that this interaction is more easily disturbed in HCV infection than other KIR-HLA interactions. Simply put, as an analogy to a car, it is like taking your foot off the brake of the natural killer cell rather than pressing the accelerator in order to get it going. This may then kick-start the rest of the immune response to HCV.’

By studying how people acquired HCV infection, the findings also suggest that the amount of virus they received is an important factor. Data suggests that the mechanism that researchers have discovered is more important in people receiving lower infectious amounts of HCV. The protective effect of genes on the virus was observed in Caucasians and African Americans with expected low infectious doses of HCV, but not in those with high-dose exposure, in whom the innate immune response is probably overwhelmed.

Dr Khakoo continued: ’We believe that this study is a significant advance in the understanding of hepatitis C virus infection. There are other interesting outcomes from our research. It implicates NK cells, and the innate immune system in general, in clearing HCV infection and this has not previously been clearly documented. It also suggests that the more NK cells of the protective type that an individual has the more likely they are to clear HCV.’

The researchers believe that the findings could eventually lead to new treatment strategies for HCV based around NK cells in general and KIR2DL3/HLA-C in particular.