Study examines ways to restore immunity to chronic hepatitis C infection

September 3, 2013

The hepatitis C virus hijacks the body's immune system, leaving T cells unable to function. A new study in animal models suggests that blocking a protein that helps the virus thrive could restore immune function, allowing the body to fight infection. The work, led by teams at The Research Institute at Nationwide Children's Hospital and Emory University, was published online Aug. 26 in the Proceedings of the National Academy of Sciences.

Previous studies show that antibody treatments that inhibit the protein, called programmed cell death 1 (PD-1), can shrink tumors in humans. This new work suggests that anti-PD-1 antibodies might be equally effective in treating hepatitis C and other persistent human viral infections, says Christopher Walker, PhD, a senior author on the study and director of the Center for Vaccines and Immunity at Nationwide Children's.

PD-1 is a that helps keep the immune system in check. Normally, PD-1 acts as a switch to turn off immune responses when an infection is under control. Some viruses such as HCV manipulate the PD-1 off switch so that T lose their ability to fight the infection, a condition scientists call "T-cell exhaustion." The result is life-long persistence of HCV in the liver, which increases the risk of cirrhosis, and other serious diseases.

The researchers treated animal models with persistent HCV infection with repeated doses of an anti-PD-1 antibody. Although the responses were mixed, one animal did show a dramatic increase in HCV-specific T cell activity in the liver and a sharp decrease in . A closer examination of the data found that the animal had more HCV-specific T cells in the liver before therapy, which could mean that therapeutic success hinges on the amount of HCV-specific T cells in the liver before treatment.

"Our supposition is that these T cells remained in the liver for years at levels too low to detect before treatment, and had the capacity to expand after treatment," Dr. Walker says. "The animal that responded to therapy had a broad, strong response during the early acute phase of infection. This suggests that one predictor of response to an anti-PD-1 antibody is the quality of the T-cell response when the initial infection occurs."

Another interesting finding was the impact of the antibody on CD4+ T cells, helper cells that promote the development of killer T cells called CD8+, which target and destroy virus-infected liver cells. One hallmark of chronic HCV is the collapse of CD4+ cells.

"We have no information on whether PD-1 signaling is a primary mechanism for silencing helper cells, so recovery of the CD4+ helper cell response in this instance provides some indirect evidence that PD-1 signaling also impairs the helper cells," Dr. Walker says.

Because much of the research focus on HCV is now directed at developing antiviral therapies, it's likely that these new findings may have a greater impact on treatments for chronic hepatitis B (HBV), rather than the virus studied in this experiment, Dr. Walker says.

"Chronic hepatitis B is an even larger public health problem than HCV and direct-acting drugs control but do not eliminate the virus," he says. "Immune reconstitution is the holy grail for HBV."

Toward that end, Dr. Walker's team plans to explore the insight this new study provides into why anti- PD-1 antibody therapy sometimes succeeds and sometimes fails. Specifically, they want to know what role the quality of T-cell immunity before treatment plays in therapeutic response.

"There is wide variation in the strength of T-cell immunity when people are first infected with the virus, ranging from very strong and sustained to none," notes Dr. Walker, who also is a professor of pediatrics and molecular virology, immunology, and medical genetics at The Ohio State University.

"Those with very strong sustained responses tend to clear the virus. Anything less, and the virus persists," Dr. Walker says. "This study suggests that if your T-cell response to the initial infection is good, but not enough to clear the virus, then you may respond to PD-1 blockade years later. If your initial acute phase T cell response is limited and weak, there is less opportunity for PD-1 blockade to work."

Explore further: New focus to combat rising liver disease

More information: Fuller MJ, Callendret B, Zhu B, Freeman GJ, Hasselschwert DL, Satterfield W, Sharpe AH, Dustin LB, Rice CM, Grakoui A, Ahmed R, Walker CM. Immunotherapy of chronic hepatitis C virus infection with Q:1 antibodies against programmed cell death-1 (PD-1). Proceedings of the National Academy of Sciences. Epub Aug. 26, 2013.

Related Stories

New focus to combat rising liver disease

July 26, 2013
University of Adelaide researchers are investigating how the liver responds to hepatitis C virus (HCV) and why some people can control the virus while others can't. The aim is to find better therapies to combat hepatitis ...

Helper T cells, not killer T cells, might be responsible for clearing hepatitis A infection

July 16, 2012
Helper cells traditionally thought to only assist killer white blood cells may be the frontline warriors when battling hepatitis A infection. These are the findings from a Nationwide Children's Hospital study appearing in ...

Researchers develop first successful laboratory model for studying hepatitis C

August 2, 2013
By differentiating monkey stem cells into liver cells and inducing successful infection, researchers from the Icahn School of Medicine at Mount Sinai have shown for the first time that the hepatitis C virus (HCV) can replicate ...

'Pep talk' can revive immune cells exhausted by chronic viral infection

December 13, 2011
Chronic infections by viruses such as HIV or hepatitis C eventually take hold because they wear the immune system out, a phenomenon immunologists describe as exhaustion.

New study on hepatitis C virus entry factor: Researchers identify disruption of iron uptake receptor

June 10, 2013
Hepatitis C virus (HCV) infects more than 170 million people worldwide. Approximately 80 percent of infections lead to chronic illness including fibrosis, cirrhosis, cancer and also hepatic iron overload. A new study completed ...

Study finds how the immune system responds to hepatitis A virus

June 20, 2011
A surprising finding in a study comparing hepatitis C virus (HCV) with hepatitis A virus (HAV) infections in chimpanzees by a team that includes scientists from the Texas Biomedical Research Institute sheds new light on the ...

Recommended for you

Anti-malaria drug shows promise as Zika virus treatment

November 17, 2017
A new collaborative study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) and UC San Diego School of Medicine has found that a medication used to prevent and treat malaria may also be effective ...

Decrease in sunshine, increase in Rickets

November 17, 2017
A University of Toronto student and professor have teamed up to discover that Britain's increasing cloudiness during the summer could be an important reason for the mysterious increase in Rickets among British children over ...

Scientists identify biomarkers that indicate likelihood of survival in infected patients

November 17, 2017
Scientists have identified a set of biomarkers that indicate which patients infected with the Ebola virus are most at risk of dying from the disease.

Research team unlocks secrets of Ebola

November 16, 2017
In a comprehensive and complex molecular study of blood samples from Ebola patients in Sierra Leone, published today (Nov. 16, 2017) in Cell Host and Microbe, a scientific team led by the University of Wisconsin-Madison has ...

Study raises possibility of naturally acquired immunity against Zika virus

November 16, 2017
Birth defects in babies born infected with Zika virus remain a major health concern. Now, scientists suggest the possibility that some women in high-risk Zika regions may already be protected and not know it.

A structural clue to attacking malaria's 'Achilles heel'

November 16, 2017
Researchers from The Scripps Research Institute (TSRI) and PATH's Malaria Vaccine Initiative (MVI) have shed light on how the human immune system recognizes the malaria parasite though investigation of antibodies generated ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.