As the HIV virus glides out of a human cell to dock and potentially inject its deadly payload of genetic code, there is a spectacularly brief moment when a tiny piece of its surface cracks open and the infection process begins. Capturing this structure in the fraction of a millionth of a second provides the researchers at the Duke Human Vaccine Institute (DHVI) a new grasp on the virus’s surface, which could lead to largely neutralizing antibodies for an AIDS vaccine. Their findings appear in Science Advances on February 2nd.
Crucial would be to be able to attach an antibody specifically to that small structure that prevents it from bursting. Their findings appear in Science Advances on February 2nd.
The moving part is a structure called the envelope glycoprotein, and AIDS researchers have been trying to figure this out for years, as it’s a key part of the virus‘ ability to dock to a human T cell receptor called CD4.
„Anything everyone’s ever done to stabilize this (structure) won’t work because of what we’ve learned. It’s not that they’ve done anything wrong; we just didn’t know it was evolving that way.“
Rory Henderson, lead author, structural biologist and associate professor of medicine at DHVI
The findings of the movable structure protect the delicate co-receptor binding site of the virus. „It’s also a gate that prevents it from jumping until it’s ready to jump,“ Henderson said. Holding it in place with a specific antibody can stop the infection process.
To see the viral parts in different open, closed, and intermediate states, Bennett and Henderson used an electron accelerator at the Argonne National Laboratory outside Chicago, which generates X-rays in wavelengths that can resolve something as small as a single atom. But this expensive, shared equipment is in high demand. The AIDS researchers were allocated three 120-hour blocks on the synchrotron to collect as much data as possible in marathon sessions. „Basically, you just go until you can’t go anymore,“ Bennett said.
Previous work elsewhere argued that antibodies were being developed for the wrong shapes of the virus, and this work suggests that was probably correct.
„The question was: Why are we getting antibodies at places that should actually be blocked when we’re vaccinating?,“ Henderson said. Part of the answer is likely to lie in this particular structure and its change in shape.
„It’s the interplay between the antibody binding and this shape that is really critical to our work,“ Henderson said. „And that’s what led us to design an immunogen on the day we returned from the first experiment. We think we know how this works.“
This research was supported by the National Institutes of Health (UM1AI14437, R01AI145687, U54AI170752, P30 GM124169, S10OD018483), the Department of Energy (DE-AC02-06CH11357), and the DOE Office of Biological and Environmental Research.
Bennett, AL, et al. (2024) Microsecond dynamics govern HIV-1 envelope conformation, Science Advances. doi.org/10.1126/sciadv.adj0396.