Scientists see ultra-rapid movement on the surface of the HIV virus

As the HIV virus slips out of a human cell to anchor itself and eventually inject its deadly cargo of genetic code, there is an incredibly brief moment in which a tiny piece of its surface opens to begin the infection process.

Seeing this structure open and close in millionths of a second gives investigators at the Duke Human Vaccine Institute (DHVI) a new approach to the virus surface that could lead to the production of broadly neutralizing antibodies for an AIDS vaccine . Their conclusions appear in Scientists progress.

Being able to attach an antibody specifically to this small structure that would prevent it from opening would be key.

The moving part is a structure called an envelope glycoprotein, and AIDS researchers have been trying to understand it for years because it is a key part of the virus’s ability to dock on a T-cell receptor called CD4. Many parts of the envelope are constantly moving to evade the immune system, but vaccine immunogens are designed to remain relatively stable.

“Everything that everyone has done to try to stabilize this (structure) is not going to work, because of what we have learned,” said lead author Rory Henderson, a structural biologist and associate professor of medicine at DHVI. “It’s not that they did anything wrong; it’s just that we didn’t know it was moving that way.”

Ashley Bennett, a postdoctoral researcher and co-author of the study, offers an explanation: As the virus looks for its best attachment point on a human T cell, the host cell’s CD4 receptor is the first thing it goes to. ‘hook. This connection is what then triggers the opening of the envelope structure, which in turn exposes a binding site to the co-receptor “and that’s the event that really matters.”

Once the two virus molecules are bound to the cell membrane, the process of injecting the viral RNA can begin. “If it gets into the cell, your infection is now permanent,” Henderson said.

“If you get infected, you’ve already lost the game because it’s a retrovirus,” Bennett admits.

The mobile structure they found protects the sensitive co-receptor binding site of the virus. “It’s also a latch that keeps it from springing out until it’s ready to do so,” Henderson said. Keeping it locked with a specific antibody would stop the infection process.

To observe the viral parts in various open, closed and intermediate states, Bennett and Henderson used an electron accelerator at Argonne National Laboratory outside Chicago, which produces X-rays in wavelengths capable to solve something as small as a single atom. But this shared and expensive equipment is in high demand. The AIDS researchers were assigned three 120-hour blocks with the synchrotron to try to get as much data as possible during marathon sessions. “You basically keep going until you can’t anymore,” Bennett said.

Previous research elsewhere had argued that the antibodies were designed for the wrong forms of the virus and this work shows that was probably correct.

“The question has been ‘why, when we immunize, are we getting antibodies in places that are supposed to be blocked?’” Henderson said. Part of the answer should lie in this particular structure and its transformation.

“It’s the interaction between the binding of the antibody and its shape that’s really critical to the work we’ve done,” Henderson said. “And that led us to design an immunogen the day we came back from the first experiment. We think we know how it works.”