Two physician scientists at East Tennessee State University and the James H. Quillen Veterans Affairs Medical Center (VAMC) who are studying hepatitis C have received a $1.4 million grant from the National Institutes of Health (NIH) to pursue a new direction as they try to crack the code of the virus.
Dr. Zhi Q. Yao and Dr. Jonathan P. Moorman received the NIH grant to study a virus that affects 4 million U.S. people, has limited treatment options and no available vaccine. Yao, an associate professor of Internal Medicine at ETSU’s James H. Quillen College of Medicine, is the director of the Hepatitis Program at the Quillen VAMC and the principal investigator on the project. His co-investigator is Moorman, chief of Infectious Diseases at the VAMC and a professor of Internal Medicine at the College of Medicine and its division chief of Infectious Diseases.
Moorman and Yao began studying hepatitis C together in 2000 at the University of Virginia School of Medicine, but they have spent most of those years in Johnson City. Their work has been consistently funded by NIH, but they have primarily looked at the effect of hepatitis C on T cells, a type of white blood cell that fights infection and diseases in the human body.
New findings, however, have centered their attention to cells called monocytes, which work in concert with T cells to fight disease. Monocytes look for harmful, intruding pathogens in the body, and, when they spot them, alert the normally-dormant T cells to awaken and attack.
Moorman and Yao theorize that a recently discovered inhibitory receptor called Tim-3 disrupts the natural immune process by preventing monocytes from secreting IL-12, a key cytokine that helps T cells awaken to fight hepatitis C as a virus.
“A focus on monocytes – instead of T cells – is a branch of hepatitis C research that remains largely unexplored,” Yao said. “Most of our research has focused on T cells, and the role of monocyte function in hepatitis C has been lightly studied. Our goal is to identify molecules that could be targets for new immune therapies, or a strategy for vaccine development.
“This grant aims to discover whether Tim-3-controlled IL-12 expression by monocytes is the key to opening a new door for understanding why 85 percent of people exposed to this virus become chronically infected, and half of them fail the standard antiviral therapy.”
Yao and Moorman praised the veterans at Mountain Home who come to its Hepatology Clinic, where Yao is director and supervises care for veterans infected with hepatitis C or hepatitis B, or co-infected with HIV.
New breakthroughs in hepatitis C are needed, Moorman said, because current, long-term treatments are effective in only about 50 percent of patients. The virus hunkers down in the liver and can lead to cirrhosis, cancer, liver failure and death, and it is the most common reason for liver transplants. The lack of better treatments for hepatitis C is particularly vexing, Moorman said, because about 15 percent of patients self-cure from the virus – a sure sign that a vaccine is attainable.
“That’s the holy grail of hep-C research,” Moorman said.
Working with infected patients at the Quillen VAMC, Moorman established a blood sample database 10 years ago that has guided their research. He hopes for a discovery that could do more for patients who suffer from hepatitis C, either through antiviral treatment or a therapeutic vaccine, two projects that Yao and Moorman currently study.
“We have to have improved treatments for hep-C,” Moorman said. “The treatments have gotten better, but what we do have isn’t effective for almost half of our patients, and they can have some pretty nasty side effects. Though it’s a virus that largely attacks the liver, it can affect the whole body, especially the human immune system.”
In addition to their NIH grant funding, which falls under NIH’s intensely competitive R-01 classification, Yao also leads a pilot grant where ETSU and Wake Forest University collaborate on a project dealing with hepatitis B vaccine failure in hepatitis-C/HIV-infected individuals. Yao and Moorman were co-authors on more than 10 influential scientific papers that reported their findings in the last two years in Journal of Immunology, Journal of Leukocyte Biology, Immunology and Cell Biology, and PLoS One, among others.
Yao received the Quillen College of Medicine Dean’s Distinguished Award in Clinical Science earlier this year.