A surprising finding in a study comparing hepatitis C virus (HCV) with hepatitis A virus (HAV) infections in chimpanzees sheds new light on the nature of the body’s immune response to these viruses. The results are published online ahead of print by the Proceedings of the National Academy of Sciences (PNAS) and highlighted in a press release issued by the Texas Biomedical Research Institute in San Antonio, Texas.

Understanding how HCV becomes chronic for most people infected with the virus—whereas HAV is an infection that can always be cleared by the immune system—is very important because some 200 million people worldwide are chronically infected with HCV and are at risk for progression to cirrhosis and liver cancer.  

“Remarkably, we found that HAV was more adept at evading the innate immune response than HCV, the virus that ultimately causes chronic infections,” said Robert E. Lanford, PhD, a virologist at the Texas Biomedical Research Institute and a lead author of the study. In other words, the researchers point out, HAV is the stealthier virus when it comes to evading the innate immune response—the immune system’s first-line response against invading microorganisms—despite the lack of persistent infections.

HCV infection is usually characterized by a failure of the immune system to combat and eliminate the virus. “We suspect this failure of the immune system shares attributes with other persistent viruses, such as HIV and hepatitis B virus,” Lanford said.

By comparing two similar viruses that infect the liver, one that is always cleared by the immune system, HAV, and one that frequently evades the immune response, HCV, the team hoped to unravel the mystery of how HCV causes lifelong persistent infections.

The new study points out the critical need for more information about how the immune system reacts to HCV. It also reinforces the importance of chimpanzee research in this effort. The chimpanzee, the only animal model susceptible to HCV infection, was critical for probing the molecular differences in gene expression in the liver related to infection by the two viruses.

Examination of the adaptive immune response—immune system cells trained to respond to disease-causing microorganisms—found that the T-cell response to HAV was unique as well. “We expected the immune response to kill all HAV infected cells in a short time frame, and yet we could detect the genome of the virus in the liver for up to one year, long after symptoms of the disease were resolved,” Lanford explained.

“Hepatitis viruses have co-evolved with humans over a very long period of time, and they are good at evading the immune system, but nobody understands how hepatitis C becomes a chronic infection,” said Stanley Lemon, MD, of the University of North Carolina and another researcher associated with the study. The one thing that is clear, the researchers conclude, is that “HAV infections represent a distinctly different paradigm in virus–host interactions within the liver.”