BioWorld International Correspondent

A new glimmer of understanding into how some people infected with hepatitis C virus manage to shed the infection has boosted the chances that scientists might one day be able to develop vaccines or better treatments.

New research shows that the genes that encode receptors present on the cells of the immune system help to dictate whether someone can clear HCV infection. The work, by a team of international researchers, demonstrates that one particular combination of those genes increases the chance of beating HCV.

However, that was true only for people who became infected as a result of a relatively low dose of the virus - by sharing needles for intravenous drug injection, for example, or through a needle-stick injury. It seems that the virus still wins against the immune system in those infected by a large dose, such as during blood transfusion.

The genotypes involved are those encoding the major histocompatibility complex (MHC) genes (also known as the human leukocyte antigens, or HLA), and those encoding receptors on cells of the innate immune system, called natural-killer (NK) cells.

Mary Carrington, principal investigator at the Laboratory of Genomic Diversity at the National Cancer Institute in Bethesda, Md., told BioWorld Today: "What we found was that genotypes associated with low inhibition of NK cells were protective. This tells us that NK cells play an important role in clearance of HCV, and if we could find some way to activate NK cells in individuals infected with HCV, maybe we could improve the chances of those individuals clearing the virus."

Carrington, working with Salim Khakoo from the Division of Infection, Inflammation and Repair at Southampton University in the UK, and collaborators from several centers in the U.S. and the UK, reported the findings in the Aug. 6, 2004, issue of Science in an article titled "HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection."

Carrington's group had for some time been studying variations in two clusters of genes - the MHC genes on chromosome 6 and the killer-cell immunoglobulin-like receptor (KIR) genes on chromosome 19. They wanted to understand the effects of variations in those genes on different types of human diseases.

The KIR genes encode receptors on NK cells, which help regulate the activity of the cells. NK cells are regulated by both inhibitory and activating signals, and only spring into action - killing virus-infected cells and activating other cells of the immune system - when activating signals outweigh inhibitory ones.

The role of the MHC genes is to encode proteins on the cell surface, in order to present antigenic peptides to cytotoxic T cells with the aim of stimulating them to kill infected cells or tumor cells. The MHC proteins also are ligands for the KIR proteins on NK cells, and thus help to regulate NK-cell activity.

Having already done work on how those genes affect people's responses to HIV and diseases associated with autoimmunity, Carrington and collaborators turned their attention to HCV. Worldwide, about 180 million people are infected with HCV and about 20 percent of those infected clear the virus. But the infection also can lead, decades later, to liver failure and liver cancer.

Carrington said: "We had samples from people who had been infected with HCV available to us, and because NK cells, which express the KIR genes, are found at fairly high levels in people infected with HCV, we thought it would make good sense to look at the variation of the receptors on the NK cells."

They looked for variation in the KIR genes and the MHC genes in 685 people with persistent HCV infection and 352 who had been infected with HCV but had cleared the virus.

"We found that a specific genotype in the MHC genes, combined with a specific genotype in the KIR genes, was associated with protection," Carrington said. "People with this combination were more likely to have cleared the virus."

That compound genotype, the researchers knew, had the ability to send a weak inhibitory signal to the NK cells.

"This is not so surprising," Carrington said. "Genotypes that are known to relay a strong inhibitory signal to NK cells were more common in individuals who had persistent infection. Clearly, less inhibition is an advantage here."

It now will be important for researchers to examine how those findings fit in with what is known about how NK cells function in HCV infection, Carrington added.

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