Protein kinase R is one of the most potent weapons in a cell’s protective arsenal. The enzyme lies dormant until triggered by a replicating virus. Then, it springs into action, shutting down protein production inside the cell, effectively halting viral replication. HHMI early career scientist Harmit Malik recently discovered how one virus outwits this defense mechanism by bulking up its genome.
The vaccinia virus uses two proteins—E3L and K3L—to fend off protein kinase R. E3L prevents protein kinase R activation, while K3L interferes with the enzyme’s ability to stop growth and division. Malik’s team at the Fred Hutchinson Cancer Research Center infected cells with a strain of virus lacking E3L and watched the virus evolve. After just a few rounds of replication, the virus learned how to outfox protein kinase R.
Investigating the evolved virus’s genome, the researchers saw increased numbers of K3L genes. By increasing K3L gene copies, the virus not only produces more K3L proteins to combat protein kinase R, it also enhances the probability that K3L will acquire a mutation that makes it a better weapon. Once the virus has the desirable amino acid substitution, the number of K3L genes declines. The group published their findings August 17, 2012, in Cell.
Malik plans to look for other adaptation-driven gene expansions that enable viruses to keep pace in such arms races.