One of the many tricks the AIDS virus, HIV, uses to proliferate so aggressively is it hides from the body’s immune system. Until now, this has largely been a mystery.
One of the many tricks the AIDS virus, HIV, uses to proliferate so aggressively is it hides from the body’s immune system. Until now, this has largely been a mystery. But researchers with the University Of Montreal, University of Melbourne and others have identified an important mechanism for how HIV plays this disappearing trick. They published their work recently in the journal Cell & Host Microbe.
The mechanism is related to the glycoprotein that makes up the envelope, or outer layer, of the virus. It is the proteins on these envelopes—and on most viruses and bacteria—that the immune system reacts to. But the HIV-1 envelope protein, called HIV-1 Env, is flexible, taking on different shapes. The research team identified a new shape. Before, they were aware of three separate conformations that the envelope protein used to push its way into T-cells, but “we didn’t know that this [fourth] conformation actually existed,” Andres Finzi, one of the study’s lead authors, a microbial immunologist at the University of Montreal, told STAT. “And we know the virus hates it.”
State 1 is a closed conformation, that is mostly resistant to the immune system. Binding with CD4 induces State 2. State 3 comes immediately after the CD4 binding, and is an open conformation “that is susceptible to engagement by antibodies that recognize otherwise occluded epitopes,” the authors write.
The researchers have dubbed the fourth conformation State 2A. It is not common for the HIV-1 virus to actually use this shape, but it appears to be the shape the virus uses to hide from the immune system.
In an approach that seems counterintuitive, Finzi and his colleagues forced the envelope protein into the 2A conformation. This seemed to allow the immune system to recognize the virus, and as such, they believe it might be a way to induce the body’s immune system to target the virus.
Paolo Lusso, a virologist with the National Institutes of Allergy and Infectious Disease, who was not involved in the study, told STAT, “These molecules breathe, and they’re not static. 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.”
Lusso is referring to a new imaging technique the researchers used, which can track single molecules. It is called cryoelectron microscopy. The research group imaged how HIV particles interact with the CD4 receptor on human cells, which is a little bit like a doorknob the virus uses to enter the cells. While imaging this interaction, the group noted that the envelope protein changed shape from a closed, bud-like conformation to one more like a flower blossoming.
In addition, they found that two antibodies, as well as CD4, helped the virus take on this new shape. But, once HIV entered the cells, it takes the CD4 receptor molecule in with it. That, the researchers say, makes it difficult to replicate the new shape naturally.
The researchers used a small molecule that imitates CD4 in a mixture with two antibodies. This kept the envelope in the State 2A conformation.
This cocktail of factors leads to this structural state that had never been observed,” James Munro, a molecular biologist at Tufts University and the third lead author of the study, told STAT.
Their next step was to use blood samples from nine people with HIV infections to observe the new conformation. The patients already had the two antibodies. Finzi told STAT, “We have pieces of the puzzle, but we need an initial kick.”
That kick was to add the CD4 imitation molecule to the blood samples. And voila!, the envelope protein stayed in the State 2A conformation. And that exposes some of the virus that would trigger an immune response.
Although very early, the identification of this fourth conformational state has the potential to lead to improvements in immune response to HIV infections. At the moment, this conformation is difficult to induce and the likelihood of replicating it in patients is far down the road. Still, as the field of immunotherapy advances, this is an important step.
