Study spurs new progress on AIDS vaccines
Efforts to prevent AIDS have been hampered by a biological roadblock: the failure of experimental vaccines to spur the production of effective antibodies against HIV-1, the virus that causes AIDS in humans.
When HIV-1 enters the body, it mutates rapidly. In just one week, it evolves more in a single individual than the influenza A virus does in an entire year all over the world. The immune system responds with antibodies that head for specific bits of protein known as epitopes on the viral surface. To be effective, the antibodies must bind to sections of the virus that cannot change.
Scientists have tried to target just such an area: a patch of protein called GP41 – specifically, a section known as the membrane-proximal external region (MPER). They have fastened a piece of the MPER to protein scaffolds that were injected as vaccines into animals. The resulting antibodies, it was hoped, would cripple the viruses carrying the epitope, preventing HIV-1 from entering cells.
When this technique was tested in animals, however, something puzzling occurred: the antibodies were able to recognize and bind to the scaffold and the MPER epitope, but they failed to neutralize the virus.
Now, a research team at Dana-Farber, Harvard and Northeastern universities, and the National Institutes of Health has uncovered the reason for the antibodies’ seeming ineptitude – reinvigorating a promising line of study in AIDS vaccines and suggesting that antibodies may one day be used as precision tools for performing “surgery” on cell membranes. Their study in Nature Structural & Molecular Biologydescribes the discovery and its implications for future advances against AIDS and other diseases.
Researchers led by Dana-Farber’s Mikyung Kim, PhD, and Ellis Reinherz, MD, examined the interaction between the MPER and a key antibody, 2F5, in extreme detail, finding it to be far more intricate than previously thought – a complex, dynamic encounter in which both structures are subtly reshaped.
“GP41 and the GP120 subunit attached to it are the only viral proteins exposed on the surface of HIV-1,” says Reinherz, the study’s senior author. The bits of protein serve as the virus’s hook for snaring human cells: when the hook binds to its receptor on a cell, the cell and virus fuse, setting the stage for the virus to enter the cell and tamper with its genetic program.
Reinherz and his associates knew that the 2F5 antibody homes in on a “core” section of GP41, a kind of molecular sweet spot at the base of the epitope, where it emerges from HIV-1’s surface. Using nuclear magnetic resonance spectroscopy, electron paramagnetic resonance, and hydrogen-deuterium exchange mass spectrometry, the team took a close-up look at 2F5’s coupling with the MPER.
They learned that the antibody interacts with sections of the MPER beside the core region, and found the interaction dramatically changes the shape and structure of 2F5: a looped segment of the antibody becomes a scoop for pulling up an otherwise hidden part of GP41 from the viral surface. Only when it accesses that buried region can the antibody render the virus harmless – much as a munitions expert defuses a bomb by first exposing its inner wiring.
“The discovery solves the paradox of why antibodies generated in response to the core region of the antibody have proven ineffective in neutralizing HIV-1,” says Kim, the study’s first author. More research is needed to learn whether vaccines based on larger sections of GP41 can better protect against HIV-1 infection.
Antibodies’ ability to change the structure of their target molecule is not limited to 2F5. The new study raises the possiblity that antibodies can function as “nanotools” – tiny knives or extractors – for surgically operating on the surface of individual cells, the authors say.
Contributing to the study were Dana-Farber’s Likai Song, MD, PhD, Yuxing Cheng, Shreoshi Majumdar, and Jia-Huai Wang, PhD; Kasper D. Rand, PhD, Xiaomeng Shi, and John R. Engen, PhD, of Northeastern; Zhen-Yu J. Sun, PhD, Amr F. Fahmy, PhD, and Gerhard Wagner, PhD, of Harvard Medical School; and Gilad Ofek, PhD, Yongping Yang, PhD, and Peter D. Kwong, PhD, from the National Institutes of Health. The multidisciplinary tem was funded by the Division of AIDS at the National Institute of Allergy and Infectious Disease and the Bill & Melinda Gates Foundation.
