Researchers led by Howard Hughes Medical Institute Investigator Stephen Harrison, PhD, and Bing Chen, PhD, focused on the gp120 protein, part of HIV's outer membrane, or envelope. gp120's job is to recognize and bind to the so-called CD4 receptor on the surface of the cell HIV wants to infect. Once it binds, gp120 undergoes a shape change, which signals a companion protein, gp41, to begin a set of actions that enable HIV's membrane to fuse with the target cell's membrane. This fusion of membranes allows HIV to enter the cell and begin replicating.
The structure of gp120 after it binds to the CD4 receptor and changes its shape was solved several years ago by another group. Harrison and Chen have now described gp120's structure before the shape change, yielding vital before-and-after information on how the molecule rearranges itself when it encounters the CD4 receptor.
"Knowing how gp120 changes shape is a new route to inhibiting HIV – by using compounds that inhibit the shape change," says Harrison. He notes that some HIV inhibitors already in development seem to inhibit the shape change; the new findings may help pin down how these compounds work and hasten their development into drugs. "The findings also will help us understand why it's so hard to make an HIV vaccine, and will help us start strategizing about new approaches to vaccine development."
The studies, performed in the Children's Hospital Boston Laboratory of Molecular Medicine, used the closely related simian immunodeficiency virus (SIV) as a stand-in for HIV. By aiming an X-ray beam through a crystallized form of gp120, they obtained the first high-resolution three-dimensional images of the protein in its unbound form. They surmounted considerable technical challenges, including difficulty in getting gp120 to form good crystals.
"Without very well-ordered crystals you get a very blurry picture," explains Harrison. "It took a very long time, and lots of computational work, to get that picture to sharpen up enough to get an answer."
One of the lab's first steps will be to determine which shape of gp120 – bound to the CD4 receptor, or unbound – is recognized by a person's antibodies. gp120's shape change is an important "escape mechanism" for HIV, allowing the virus to bind to and enter a cell before the immune system can "see" it, notes Harrison.
"We can now compare the bound and unbound forms and try to understand whether there are any immunologic properties that differ and that might provide a route to new vaccine or drug strategies," Harrison says.
CHILDREN'S HOSPITAL BOSTON
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults for 136 years. More than 500 scientists, including eight members of the National Academy of Sciences, nine members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. Founded in 1869 as a 20-bed hospital for children, Children's Hospital Boston today is a 325-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital visit: http://www.childrenshospital.org/research/.
HARVARD MEDICAL SCHOOL
http://www.hms.harvard.edu/
Harvard Medical School has more than 5,000 full-time faculty working in eight academic departments based at the School's Boston quadrangle or in one of 47 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Hospital, The CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, VA Boston Healthcare System.
Journal
Nature