Intact View of HIV Spike Protein Structure Achieved

Novel structural biology tools have revealed new details about the structure of human immunodeficiency virus (HIV) that help explain how it evades the immune system’s neutralizing antibodies and could lead to improved vaccines.

The findings include 3D views of the structure and position of the virus’ envelope (Env) “spike” proteins that are used when the virus binds with cells. Normally, researchers view the protein particles separated from the virus or expressed as engineered or purified proteins.  

“We’re looking at the whole virus particle and how this protein on the surface relates to the rest of the virus,” said lead author Kelly Lee, associate professor of medicinal chemistry in the University of Washington School of Pharmacy. “And by looking at the intact virus structure, we can see how the different facets of this ‘face of the virus’ are being displayed and how they would be recognized by or hidden from the immune system.”

This intact view of the virus also allowed the scientists to gain new insights into positioning of the envelope spike protein on the surface relative to the internal protein structure, called the Gag lattice.

“This finding overturns previous models of how the parts of the viruses are assembled and helps to focus our attention on where the docking interaction of these two proteins is likely to be,” Lee said. “This interaction needs to be resolved in more detail, but at least the current work gives us the correct architectural model for the virus assembly.”

The findings also indicate that the “stalk” supporting the envelope proteins is flexible and can tilt, presenting both opportunity and challenges to the immune system’s neutralizing antibodies that protect cells from infection.

HIV’s envelope presents a particularly difficult target for vaccine development, says co-corresponding author Michael Zwick, associate professor of immunology and microbiology at Scripps Research, because the virus displays so few spikes and camouflages them with sugar molecules so as to evade our immune system.

“All these features increase the dynamic variability that the HIV spike protein presents to the immune system,” adds Lee, who also directs a UW lab exploring virus structure and dynamics. “This is something that people in HIV vaccine development have grappled with from the very beginning — this virus mutates and changes itself astronomically and rapidly. Each time it infects an individual, you end up with literally thousands of different variants within that one individual, and if you look across populations, it’s multiplied even more.”

Structural biology has driven HIV vaccine design, so better pictures of what is being targeted may lead to improved vaccines, Zwick adds.

The work  was published recently in Cell.