Researchers have for the first time seen how the HIV virus enters healthy cells.
Vaccine researchers at the Duke University Human Vaccine Institute in the US used an electron accelerator to observe the lightning-quick movements of a protein on the surface of HIV, which is key to it being able to enter human T cells.
Until now, scientists haven’t been able to visualise all the steps of how this protein “latch” pops open to allow the virus to inject its genomic information.
The findings, detailed in a new paper in Science Advances, will inform the design of future vaccines to produce antibodies aimed at keeping this “latch” firmly closed.
For the HIV virus to infect T cells, a type of immune cell, a structure called envelope glycoprotein on its surface must change shape.
First, the envelope glycoprotein attaches onto a receptor on the T cell called CD4. This triggers a rapid change in shape, with the envelope glycoprotein snapping open rapidly to expose a protected co-receptor binding site.
The researchers were able to visualise the epithelial glycoprotein in its open, closed, and in-between states. They found that this shape transition happens not simultaneously, but in sequential movements.
Once the co-receptor binding site is revealed it connects with the surface of the human cell. Only then can the virus fuse with it and inject its genome into the cell.
HIV is a retrovirus, which means that when its single stranded RNA genome gets inside a human cell, it is integrated into the host’s chromosome. Once this happens the infection becomes permanent.
By understanding exactly how the envelope glycoprotein changes shape, scientists hope to design vaccines to produce antibodies that keep it in the closed position, preventing HIV from entering cells in the first place.
“Everything that everybody’s done to try to stabilise this structure won’t work, because of what we learned. It’s not that they did something wrong; it’s just that we didn’t know it moves this way,” says senior author Rory Henderson, a structural biologist and associate professor of medicine in the Duke University Human Vaccine Institute in the US.
In their paper, the authors conclude: “These results show that transient intermediate states observable only on a microsecond scale play an essential role in controlling HIV-1 [envelope glycoprotein] conformation. Blocking these early transitions is likely an important consideration in vaccine development efforts.”