How poxviruses such as smallpox evolve rapidly to become drug resistant
Washington: New research from scientists at Fred Hutchinson Cancer Research Center and collaborating institutions has uncovered how poxviruses includes smallpox evolve to rapidly adapt against host defenses – despite their low mutation rates.
The discovery provides new insight into how large, double-stranded DNA viruses evade host immunity and become drug resistant, and it has particular implications for understanding the mechanisms of infectious-disease transmission between animals and humans.
To determine the mechanisms of adaptation, senior author Harmit S. Malik, Ph.D., a member of the Hutchinson Center`s Basic Sciences Division, first author Nels C. Elde, Ph.D., a former postdoctoral researcher in Malik`s lab, and colleagues conducted an experiment in cell culture using vaccinia virus, the type of poxvirus used in the smallpox vaccine, to mimic viral adaptation and evolution as it occurs in nature.
Previous research had demonstrated that a host-defense protein called protein kinase R (PKR) is a major hurdle to poxvirus infection. In response, poxviruses have evolved to overcome PKR by encoding two genes, K3L and E3L, which thwart host-defense mechanisms that normally prevent viral infection.
The team studied how vaccinia virus, when altered to delete the E3L gene, evolved to successfully replicate in the presence of human PKR.
“Dramatically, serial propagation of this `weaker` virus rapidly resulted in strains that became much more successful at replicating in human cells,” said Malik, who is also an Early Career Scientist of the Howard Hughes Medical Institute.
Closer examination of their mode of adaptation revealed that the virus was quickly able to defeat PKR by selectively increasing the number of copies of the K3L gene in its genome.
Malik likened this rapid adaptation to the expansion of the bellows of a musical accordion.
“As the K3L copy number increased in subsequent rounds of replication, so did expression of the K3L protein and subsequent inhibition of the immune response,” he said.
This showed that viruses that can quickly expand their genome have an immediate evolutionary advantage over those that cannot.
In a further extension of the accordion analogy, in addition to observing rapid gene expansion in the E3L-deficient strain of vaccinia, the researchers also observed that the virus contracted after acquiring an adaptive mutation, swapping a beneficial mutation for a smaller genomic footprint.
“Our studies suggest that despite their transient nature, gene expansions may provide a potent means of adaptation in poxviruses, allowing them to survive either immune or pharmacological challenges,” Malik said.
Recognizing the means by which they undergo this expansion may provide more effective antiviral strategies against these and related important pathogens, the researcher added.
Their findings are described online ahead of the Aug. 17 print issue of Cell.