The images, contained in a study in the Sept. 11 issue of the Proceedings of the National Academy of Sciences, provide a detailed, close-up look at one part of the meeting between infected cells and "helper" T cells, which mobilize the body's defenses against disease. A comparison of those images with images of the meeting between helper T cells and HIV-1 (the virus that causes AIDS) shows how HIV-1 mimics other enemy invaders and essentially blindfolds the T cells to the presence of infection and cancer.
"This work enables us to piece together an exact picture of a key part of the process by which the immune system is alerted to disease, and to understand how HIV subverts that process," says the study's lead author, Jia-huai Wang, Ph.D., of Dana-Farber. "It provides a pictorial explanation for immunodeficiency - the process by which HIV undermines the immune system's ability to resist invaders. And it will help in the development of AIDS therapies that target the vulnerable points of HIV infection."
The study is the latest chapter in a scientific saga that began 20 years ago, when Dana-Farber researchers discovered a molecule called CD4 on the surface of helper T cells. CD4 serves as an antenna, enabling helper T cells to probe other cells for signs of infection and, in the case of HIV, a keyhole by which the virus gains entry to the cell and subverts its function.
When a helper T cell encounters another cell, it uses various probes on its surface - known as receptors and CD4 coreceptors - to examine protein fragments arrayed on the cell's surface. The fragments tell the T cell whether the target cell is normal, and to be left unharmed, or infected, and to be destroyed. The protein fragments are cupped inside tiny "holders" called class II major histocompatibility complexes (class II MHCs).
Two years ago, Wang and senior author Ellis Reinherz, MD, of Dana-Farber, used X-ray crystallography to produce the first three-dimensional images of a portion of the T cell receptor bound to protein fragments in a class II MHC. The new study provides the last piece of the puzzle: combined with crystallography images obtained by other researchers, scientists now have a complete structural rendering of a T cell receptor, CD4 coreceptor, and protein fragment enmeshed with a class II MHC.
The coupling, it turns out, is a rather tenuous one. Only a small corner of the CD4 molecule directly contacts the MHC. The structures appear to form a V: the T cell receptor and CD4 coreceptor spread apart from the areas of contact with the class II MHC.
The significance of this finding became apparent when researchers compared the new image with an image of CD4 bound to a protein on the surface of HIV-1.
HIV uses CD4 as an anteroom for infecting T cells. A protein on the surface of HIV, called gp120, latches onto the CD4 coreceptor, beginning a process by which HIV is ushered inside the cell.
When the Dana-Farber researchers compared the union between CD4-MHC with the one between CD4-gp120, they found that gp120 covers a greater portion of CD4. The result is helper T cells form a stronger bond with HIV than they do with cells that help protect against infections. HIV, in effect, blindfolds helper T cells to the presence of enemy invaders, hampering the body's ability to fight not only HIV itself, but other infections as well.
"We now have a graphic representation of how HIV hinders the immune response," Reinherz says. "We've known in the past that the grip between HIV and helper T cells is stronger than the one between T cells and other normal components of the body's immune system. Now we know why."
The finding offers important information in the quest for new AIDS treatments. Therapies that interfere with HIV's ability to link with helper T cells by binding to gp120, for example, might offer a promising way of preventing HIV infection while maintaining the body's natural ability to counter disease.
The work is a joint effort between Dana-Farber Cancer Institute scientists and colleagues at Argonne National Laboratory, and was supported by the National Institute of Allergy and Infectious Diseases and the U.S. Department of Energy.
Dana-Farber Cancer Institute (www.danafarber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), a designated comprehensive cancer center by the National Cancer Institute.
Proceedings of the National Academy of Sciences