|An article by Emory Vaccine Center scientists and colleagues published in the Feb. 9, 2006 issue of the journal Nature has been selected for the "All-Time Top 10" most interesting scientific papers. The Faculty of 1000 Biology website ranked the article first in its All-Time Top 10 list in immunology and fourth in its All-Time Top 10 list in "All of Biology." In addition, the paper was rated "exceptional," and was one of only a few selected for inclusion in the Faculty of 1000 Biology calendar for 2007.
The article was entitled "Restoring function in exhausted CD8 T cells during chronic viral infection."
The research was conducted in the laboratory of Rafi Ahmed, PhD, Emory Vaccine Center director and Georgia Research Alliance Eminent Scholar. Daniel Barber, PhD, an Emory graduate student at the time, was the article's first author, and Dr. Ahmed was senior author. Gordon J. Freeman of the Dana-Farber Cancer Institute was senior co-author.
The article described a new and 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.
Scientists believe the discovery of the PD-1 pathway 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 to persist and that makes them so difficult to treat.
PD-1 is part of a biochemical pathway activated by the interaction of the molecule PD-L1 with the PD-1 receptor. In order to block this PD-L1/PD-1 pathway, the scientists administered antibodies that blocked the PD-L1 molecule, then monitored T-cell responses and viral control. In mice receiving the blocking antibodies, the ability of CD8 T cells to multiply was greatly enhanced, the T cells secreted cytokines (proteins that prevent the growth of viruses and make cells resistant to viruses), virus-infected cells were killed, and the virus was cleared from the blood serum, the spleen and the liver. Mice not treated with the blocking antibody retained high levels of virus, while the treated mice remained healthy and did not show further signs of disease.
"The 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 says. "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."
The paper's other authors included E. John Wherry, PhD, of the Wistar Institute in Philadelphia; David Masopust, PhD, of Emory; Baogong Zhu, MD, of Dana-Farber Cancer Institute; 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 Grand Challenges in Global Health initiative, the National Institutes of Health, Howard Hughes Medical Institute, and Cancer Research Institute.
The Emory Vaccine Center, established in 1996 and located at the Yerkes National Primate Research Center, is one of the world's largest and most successful academic vaccine centers. Over the past decade the Vaccine Center has attracted more than $200 million in external research funding. The Center employs 39 faculty researchers and nearly 200 postgraduate students and staff developing vaccines for HIV/AIDS, hepatitis C, malaria, influenza and other global disease threats.
Faculty of 1000 Biology is an award-winning online service that highlights and evaluates the most interesting papers published in the biological sciences, based on the recommendations of over 2,000 of the world's top researc hers. Papers are highlighted on the basis of their scientific merit. The site was launched in January 2002. For more information, visit http://www.f1000biology.com/about.