When the HIV virus "slips" outside the body's cells to dock and inject its deadly genetic code, there is an extremely brief buffer time, and then a small piece of its surface suddenly opens up and begins to infect.
Seeing this structure open and close in just a millionth of a second, researchers at the Duke Human Vaccine Institute (DHVI) offer a new direction on the surface of the virus, potentially developing antibodies to the AIDS vaccine. Their findings were published in the Feb. 2 issue of the journal Science Advances.
Being able to attach the antibody specifically to this small structure to prevent it from suddenly opening will be key.
The HIV-1 ENV glycoprotein is structurally dynamic.
The mobile moiety is a structure called an envelope glycoprotein, which AIDS researchers have been trying to figure out for years because it is a key part of the virus's ability to dock with a T-cell receptor called CD4. Many parts of the envelope are constantly moving to evade the immune system, but vaccine immunogen is designed to remain relatively stable.
Lead author Rory Henderson, a structural biologist and associate professor of medicine at DHVI, said: "Because of what we know, everything that everyone does to stabilize this [structure] won't work," said lead author Rory Henderson, a structural biologist and associate professor of medicine at DHVI. It's not that they're doing anything wrong, it's just that we don't know they're going to move like that. ”
"When a virus looks for the best attachment site on a human T cell, the host cell's CD4 receptor is the first thing it attaches to," said Ashleybennett, postdoctoral researcher and study co-author. This connection then triggers the ejection of the envelope structure, which exposes the co-receptor binding site, which is what really matters. ”
Rory Henderson continues: "Once both molecules of the virus have bound to the cell membrane, the process of injecting viral RNA can begin, and if it gets inside the cell, your infection is permanent. ”
"If you're infected, you've already lost the game because it's a retrovirus," Ashleybennett said. ”
The mobile structures they discovered could protect sensitive co-receptor binding sites on the virus.
"It's also a latch that prevents it from bouncing until it's ready to bounce, and locking it with a specific antibody stops the infection process," Roryhenderson said. ”
To look at the parts of the virus in open, closed, and intermediate states, Roryhenderson and Ashleybennett used an electron accelerator at Argonne National Laboratory outside Chicago, which produces X-ray wavelengths that can resolve objects as small as a single atom. But this expensive shared device is in high demand. AIDS researchers were given three 120-hour synchrotron slots to try to get as much data as possible during the marathon.
The TR, T-Jump SAXS of HIV-1 ENV reveal two structural shifts.
Ashleybennett: "Basically, you just keep doing it until you can't do it anymore. ”
Early research elsewhere suggested that antibodies were designed to target the wrong shape of the virus, and this study suggests that this may be true.
Roryhenderson: "The question is, 'Why do we produce antibodies where we should be locked down when we're immune?'" Part of the answer lies in this particular structure and its deformation. The interaction between antibody binding and shape is critical to the work we do. This prompted us to design an immunogen on the day we came back from the first experiment. We think we know how it works. ”
Data**: Bennett, Al.,etal.(2024)microseconddynamicscontrolthehiv-1envelopeconformation.scienceadvances.