Two new studies reveal how US scientists managed to uncover the detailed structure of a protein that plays a key role in HIV infection. The findings offer the kind of in-depth understanding that has been missing in the development of successful vaccines against the AIDS virus.
Using protein engineering and two different cutting-edge structural biology imaging techniques, collaborating teams from The Scripps Research Institute (TSRI) and Weill Cornell Medical College have revealed a detailed atomic structure of the HIV envelope trimer known as Env.
The new discovery is documented in two studies, both published online in Science this week.
None of the HIV vaccines tested so far has come close to giving enough protection, a failure that is largely due to the challenges posed by Env.
Env is a three-part protein (a trimer) found on the surface of HIV that is critical to understanding how the virus gets into human cells to cause infection.
Env has evolved highly effective ways of avoiding attack by the immune system. For instance, it frequently mutates its outermost regions, and it also coats its surfaces with very slippery sugar molecules called glycans.
The more scientists know about Env and its structure, the higher the chances of developing successful vaccines.
It has been difficult to get atomic-level resolution images of the Env protein because its structure is complex and delicate – but now new techniques have now made this possible.
First, to capture the image, the teams engineered a more stable version of the protein, as one of the senior authors Andrew Ward, an assistant professor in TSRI’s Department of Integrative Structural and Computational Biology, explains:
“It tends to fall apart, for example, even when it’s on the surface of the virus, so to study it we have to engineer it to be more stable.”
Then, having stabilized the Env trimer, using cryo-electron microscopy and X-ray crystallography, the scientists were able to discover its structure and also how it assembles and engages with HIV antibodies.
One aspect of the discovery that will be of great help to vaccine developers is knowing the precise details of the sites where HIV antibodies can bind to the virus – so they can mimic these viral “epitopes” with the vaccine.
Another senior author, Ian A. Wilson, the Hansen Professor of Structural Biology at TSRI, says:
“Most of the prior structural studies of this envelope complex focused on individual subunits, but we’ve needed the structure of the full complex to properly define the sites of vulnerability that could be targeted, for example with a vaccine.”
Funds from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, helped finance the studies.
In another recently published study, researchers from the University of Florida and the University of California, San Francisco, describe how cats may be key to HIV vaccine. They found that blood from patients infected with HIV showed an immune response against a feline AIDS virus protein.