NIAID researchers have found a new explanation for the evolutionary factors that drive antigenic drift of influenza viruses. They report that high- and low-affinity influenza virus mutants alternate depending on the extent an individual has been exposed to flu viruses. The research appears in Science.
It is not possible to dissect the mechanism of antigenic drift in people directly, notes Jonathan W. Yewdell, M.D., Ph.D., one of the researchers who led the study. So he and his colleagues turned to a mouse model developed in the mid-1950s at the University of Chicago. The team infected mice with a strain of seasonal influenza virus that had circulated in Puerto Rico in 1934. Some mice were first vaccinated against this virus strain and developed antibodies against it.
After infecting the vaccinated and unvaccinated mice with the 1934 influenza strain, the scientists isolated the virus from the lungs of both sets of mice and passed on these viruses to a new set of mice. They did this nine times. After the final passage, the researchers sequenced the gene encoding the virus hemagglutinin protein. Hemagglutinin forms the major outer coat of the flu virus, and antibodies recognize one or more of the four antigenic regions in it.
Sequencing revealed that the unvaccinated mice had no mutated influenza viruses in their lungs. In contrast, the hemagglutinin gene isolated from vaccinated mice had mutated in a way that increased the ability of the virus to adhere to the receptors it uses to enter lung cells. Essentially, says Dr. Yewdell, the virus can shield its hemagglutinin antigenic sites from antibody attack by binding more tightly to its receptor. “The virus must strike the right balance, however,” he points out. “Excessively sticky viruses may end up binding to cells lining the nose or throat or to blood cells and may not make it into lung cells.
“Also, newly formed viruses must detach from infected cells before they can spread to the next uninfected cell. Viruses that have mutated to be highly adherent to the lung cell receptors may have difficulty completing this critical step in the infection cycle.”
Next, the researchers infected a new set of unvaccinated mice with the high-affinity mutant virus strain that had emerged in the first series of experiments. In the absence of antibody pressure, the virus reverted to a low-affinity form and was once again able to easily infect cells and spread.
“We propose a model for antigenic drift in which high- and low-affinity influenza virus mutants alternate,” says Dr. Yewdell. In adults who have been exposed to many strains of influenza in their lifetime and, correspondingly, have a wide range of antibody responses, the virus is pressured to increase its receptor affinity to escape antibody neutralization.
“Our model predicts that decreasing the immunologically naive population by increasing the number of children vaccinated against influenza, for example, could slow the rate of antigenic drift and extend the duration of effectiveness of seasonal influenza vaccines,” Dr. Yewdell concludes.