"The HR1 basically resembles a highly bent twig that is ready to spring back straight," said Kong. "This small bend in the HR1 region is likely ground zero for metastability. In most published Env structures, this region appears disordered when mutated or loosely packed when in its native form. From these observations, it seemed reasonable that rewiring the HR1 bend could greatly stabilize Env."

Indeed, when the scientists tweaked HIV's genetic sequence, they were able to shorten the HR1 region, preventing its transformation and keeping the rest of the structure stable.

"We've figured out one of the fundamental reasons why HIV is metastable," said Zhu.

The researchers then demonstrated that their stabilized Env trimers also almost perfectly mimicked the structure of the real HIV trimer, suggesting they could be useful in vaccines. Since rewiring the HR1 should prevent Env undergoing its necessary shape-shifting changes to infect cells, the stabilization strategy also could lead to protein or DNA-based vaccines. Furthermore, the modified trimer also has the potential to be produced in reasonably large quantities and at high purity--important considerations in industrial-scale vaccine production.

Finally, since many viruses contain metastable Env proteins with HR1-like regions, this TSRI-developed engineering approach may be applicable in the design of vaccines against other viral pathogens such as influenza and Ebola virus.