Scientists have identified a simple but highly effective strategy for boosting the immune response to chronic viral infections in mice. By blocking a specific molecular pathway in the mouse immune system called PD-L1/PD-1, the scientists were able to enhance production of CD8 T cells, kill virus-infected cells, and decrease the viral load. The discovery may help overcome the challenging hurdle of immune T-cell "exhaustion" in humans that allows chronic viruses such as HIV and hepatitis B and C viruses to persist and makes them so difficult to treat. The research was reported in the on-line edition of the journal Nature on December 28.
The immune system responds to acute viral infections in two ways: with antibodies that help prevent the viruses from entering cells, and with an aggressive reaction by CD8 T cells that are activated to kill virus-infected cells. After a few weeks, about five percent of these immune cells become "memory cells" that are poised to mount an even stronger response to future attacks by the same virus. In chronic viral infections, however, CD8 T cells respond only during the early stages of infection, then gradually "run out of steam" as the infection endures. Scientists have not really understood exactly why these T cells lose their effectiveness.
In order to identify the specific mechanism at work in inhibiting CD8 T-cell function, scientists from Emory University School of Medicine, Harvard Medical School and the Dana Farber Cancer Institute used microarray technology to analyze and compare gene expression in CD8 T cells responding to acute and chronic viruses in a mouse model. They discovered that the gene for a receptor called PD-1 was up-regulated in the non-functioning T cells in mice infected with a chronic strain of LCMV (lymphocytic choriomeningitis virus). PD-1 was not detected, however, in the functioning memory T cells in mice infected with an acute strain of LCMV. The scientists also found that PD-1 was expressed for a short time after acute infection with LCMV but was quickly down-regulated, while PD-1 expression continued to increase in chronically infected mice.
First author of the research paper was Daniel L. Barber, PhD, a graduate student in the laboratory of senior author Rafi Ahmed, PhD, director of the Emory Vaccine Center, a Georgia Research Alliance Eminent Scholar, and professor of microbiology and immunology at Emory University School of Medicine. Gordon J. Freeman, PhD of the Dana-Farber Cancer Institute, was co-senior author.
"This research identifies a specific way in which T cells lose their functionality and points the way to a simple and effective immune strategy for treating chronic viral infections," Dr. Ahmed said. "This is an exciting discovery that will help us in designing therapeutic vaccines and drug therapies for chronic infections that have been very difficult to treat, including HIV and hepatitis C virus."
"Dysfunction of T cells is common in many chronic viral infections as well as in cancer," said Dr. Barber.
Other authors included E. John Wherry, PhD, of the Wistar Institute in Philadelphia; David Masopust, PhD, of Emory; Baogong Zhu, MD, of Dana-Farber; James P. Allison, PhD, Howard Hughes Medical Institute and Memorial Sloan-Kettering Cancer Center; and Arlene H. Sharpe, MD, PhD, Brigham and Women's Hospital.
The research was supported in part by the Bill and Melinda Gates Foundation's Grand Challenges in Global Health initiative, the National Institutes of Health, Howard Hughes Medical Institute, and Cancer Research Institute.