Hep C infection
linked to genes that suppress action of
killer immune cells
In a study to be published in Science online
Aug. 6, researchers at Johns Hopkins have found that genes involved
in suppressing the body's defensive "killer" immune cells
are a potential key factor in spontaneous recovery from hepatitis C.
The viral infection of the liver can lead to cirrhosis, cancer and
even death. This genetic factor was found in people assumed to be
exposed to a low dose of virus at the time of infection. "Our
findings may help explain why some of the 20 percent of people
infected with hepatitis C manage to recover on their own, while the
remaining 80 percent remain infected and may need treatment,"
said one of the study's lead authors, infectious disease specialist
Chloe Thio, M.D., assistant professor of medicine at The Johns
Hopkins University School of Medicine.
In determining how some patients self-recover,
the scientists hope one day to develop a vaccine and improve
therapies for hepatitis C.
"Hepatitis C infection is a serious
disease with few treatments, and it takes a heavy toll among
disadvantaged Americans, including those who have weakened immune
systems and are HIV positive," said Thio. "Our results
were surprising in that self-recovery is not so much a function of
speeding up the body's immune system to attack the hepatitis C virus
as it is about taking the foot off the brakes so the body's killer
immune cells can take off."
Using a DNA analysis of the blood from more
than 1,000 patients infected with hepatitis C, of whom 350 recovered
on their own without therapy, the researchers were able to determine
what genetic characteristics were more common in those who
self-recovered than in those who did not.
They found that the genes for a key protein, a
receptor called KIR2DL3, in combination with genes for its key
ligand, or attaching molecule called HLA, were more common in
patients who self-recovered from hepatitis C. This combination was
active only in those patients who were homozygous for this
KIR2DL3-HLA, meaning two copies of the gene, one from each parent,
were required for self-recovery to happen. Among those who received
a presumed low viral dose, two copies of the KIR2DL3-HLA receptor-ligand
combination were found in 20 percent who self-recovered from their
infection, while it was present in just 10 percent who did not
An important function of the KIR receptors is
suppressing the action of the body's killer immune cells, serving as
a chemical signal to not attack otherwise healthy cells. Conversely,
when the KIR receptors are not suppressing the immune system, the
killer immune cells can be activated and turned on to rid unwanted
cells from the body, such as bacteria and viruses like hepatitis.
The researchers focused their efforts on the
genes involved with killer immune cells because earlier studies in
animals had shown that natural killer cells were more active in
those who self-recovered from hepatitis C infection than in those
who did not.
"It remains to be explained how these
genes and viral dose at the time of
infection interact in determining self-recovery from hepatitis
Thio. "It can only be hypothesized at this point that high-dose
possibly overwhelm the body's killer immune system, whereas low-dose
infections do not."
"This study puts the spotlight on activating or not activating
inhibitory signals of the innate immune response," said a
author and infectious disease specialist David Thomas, M.D.,
medicine at Hopkins. "Whether it is possible to manipulate
specific signals to promote recovery from hepatitis C remains to be
the meantime, this finding is an important step forward in our
of hepatitis C recovery."
Funding for this multinational study was provided by the National
of Health, the Centers for Disease Control, Hope Charity and the
Research Council, National Health Service, United Kingdom.
Other investigators in this research, led by Mary Carrington at the
Cancer Institute, were Salim Khakoo, Collin Brooks and William
Southhampton University, U.K.; Maureen Martin, Xiaojian Gao, Jie
James Goedert, and Stephen O'Brien, also from the National Cancer
David Vlahov, New York Academy of Medicine; Margaret Hilgartner, New
Presbyterian Hospital-Cornell Medical Center; Steven Cox and
Little, The Royal Free Hospital, London, U.K.; Graeme Alexander,
of Cambridge, U.K.; Matthew Cramp, Derriford Hospital, Plymouth,
Jacquie Astemborski, also from Hopkins.
Hepatitis C is the leading cause of liver disease in the United
the most serious form of hepatic infection. It affects more than 4
people in the United States, with an estimated 10,000 to 12,000
year. Hepatitis C is transmitted by contact with blood and other
of an infected person, through sexual activities, injection drug
sharing of personal care items or direct contact.