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One of the many mysteries that scientists working with HIV have been trying to solve is how the virus keeps its identity hidden in the body. The virus can be detected in blood, but once it gains entry into our cells, it remains obscure and out of reach of the immune system. And this inability to detect the virus in our cells has hindered efforts to properly eliminate the disease.

But a new study’s findings suggest that we may have found a way to reveal the virus’s presence in human cells. In the study published Wednesday in Cell & Host Microbe, scientists were able to identify a new shape of an essential HIV protein that allows the virus to gain entry into our cells. And it turns out that keeping this protein — known as Envelope — in this new shape might reveal vulnerabilities within the virus to make it visible to the immune system.

Previously, scientists knew about three shapes, or conformations, that the Envelope protein uses to force its way into our cells, but “we didn’t know that this [fourth] conformation actually existed,” said Andrés Finzi, a microbial immunologist at the University of Montreal and one of the lead authors of the study. “And we know the virus hates it.”


The fourth conformation — which the scientists call State 2A — is a shape that the virus usually doesn’t adopt. It’s also how the virus seems to elude the immune system.

In the new study, Finzi and his colleagues found that forcing the Envelope protein into the 2A conformation makes the otherwise evasive HIV virus known to the immune system, and could offer a way to have the body’s own immune mechanisms target the virus.


Isabelle Rouiller/University of Melbourne in Cell Host & Microbe
Envelope proteins on the surface of HIV sabelle Rouiller/University of Melbourne in Cell Host & Microbe

Think of it as a closed can, suggests Isabelle Rouiller, a structural biologist at the University of Melbourne, who was also a lead author on the study. “With a closed can, you cannot really see what’s inside, just as the immune system cannot detect what’s inside,” she said. “But if we are able to open it, then we expose a region of the virus that the immune system can now see.”

Using a new imaging technique that allows single molecules to be tracked, the team looked at how HIV particles interact with a receptor on human cells known as CD4 to gain entry into the cell. During this process, scientists noticed that the Envelope protein went from a closed, bud-like conformation to something that resembles a blossoming flower.

“These molecules breathe, and they’re not static,” said Paolo Lusso, a virologist at the National Institutes of Allergy and Infectious Disease, who was not involved in the study. “Any progress in this field and using these new technologies is extremely interesting because it’s the first time we see this movie, almost, of a live molecule.”

The scientists also noticed that two types of antibodies, along with the help of CD4, were what seemed to help unleash this new conformation of Envelope. However, once HIV enters human cells, it also takes with it the CD4 receptor it was bound to, making the new conformation a challenge to replicate naturally. 

And so the researchers tested a three-pronged approach: A small molecule that mimics CD4 along with the two antibodies that seemed to help pry open the Envelope protein. They approach was successful in keeping Envelope in the State 2A conformation.

“This cocktail of factors leads to this structural state that had never been observed,” said James Munro, a molecular biologist at Tufts University and the third lead author on the study,

But the researchers didn’t stop there. They also used blood samples from nine HIV-infected individuals to see if they could observe the new conformation in the samples.

All nine people already harbored the two antibodies that form part of the three-pronged approach to keeping Envelope open. “We have pieces of the puzzle, but we need an initial kick,” Finzi said. The team then added the CD4 mimetic to the blood samples, and found that Envelope stayed in the State 2A conformation, exposing parts of the virus that would trigger an immune response. Since HIV-infected individuals already seem to harbor part of what could make this approach work, “This could potentially complement the current therapies that exist,” Finzi added.  

“It’s still early, but if we have a way to induce State 2A, we should be able to get better [immune response] to cure infection,” said Li Wu, an HIV researcher at the Ohio State University, who was not involved in the study. But because it’s not easy to induce this conformation, the big challenge will be to figure out a way to replicate this strategy in patients. “That can be a potential strategy to enhance current HIV therapy, but it could be a long way there.”

One immediate roadblock is that the images that the researchers were able to get are of a fairly low resolution. But Munro said that the technique used in the study — known as cryoelectron microscopy — “is becoming more and more powerful every day,” and so it likely will be possible to get a better look at what’s actually happening on the cell surface.

“With the difficulty in developing HIV vaccines, it has become clear we should also look for unconventional methods,” NIAIDS’s Lusso said, and the kind of approach laid out in the new study is a “first step” in that way forward, he says.

And the study’s authors agree that there’s still a long way to go. Finzi emphasized that the work still needs to be replicated in animal models before it can be taken to humans. “This is far from being over,” he said. “We are very excited that we now have an image to see what may be happening, but we have a lot of work still to do.”