A new study from Massachusetts Institute of Technology (MIT) explains how flu viruses' evolve so quickly. The work was published yesterday in eLife.
Many flu vaccines target the hemagglutinin protein, which is displayed on the surface of the flu viral envelope. However, because the protein can evolve quickly, the flu vaccine also needs to be changed every year. Rapid evolution is a challenge for viruses. When they evolve and their proteins mutate, sometimes they may be unable to fold into the shape they need to perform their function. Previous research has shown that in many organisms, the evolution of endogenous proteins depends on the ability of that organism's chaperones to help mutated proteins fold.
In this study, the MIT team investigated whether viruses can take advantage of their host's chaperone proteins to help with their own evolution.
"Viral proteins are known to interact with host chaperones, so we suspected that this interplay could have a major impact on what evolutionary pathways are available to the virus," senior author Matthew Shoulders explained.
To test their hypothesis, the researchers used three sets of cells. In one set they inhibited heat shock protein 90 (Hsp90), which inhibited chaperone proteins. In another set of cells, they used chemical genetic methods to enhance the levels of numerous chaperone proteins. In the last set, they had a group of cells with normal chaperone levels. When they infected all three sets with the flu virus and allowed them to evolve for about 200 generations, they found that the virus evolved faster in the cells with higher chaperone levels than in the cells with inhibited chaperone proteins.
"This finding suggests that influenza will acquire new traits that might be beneficial for it faster when you have the heat shock response activated, and slower when you have key chaperones inhibited," Shoulders says.
In addition, the researchers found the proteins that tended to become more mutated in the cells with chaperones. These proteins included hemagglutinin and an enzyme called PA. The team also identified specific amino acids within these proteins that are more likely to become mutated in different protein-folding environments.
The team believes that using chaperone inhibitors could help ensure that the virus does not evolve resistance to the therapeutic. They think that a chaperone-inhibiting drug could be used alongside an antiviral therapy.
Shoulders and the team believe that other fast mutating viruses are taking advantage of chaperones as well. Currently, they are studying HIV and also plan to study how a host cell's protein-folding capacity may affect the evolution of antiviral drug or antibody resistance, using therapeutics that circulating viruses are already resistant to.