Researchers uncover reason behind rapid evolution of poxviruses

Researchers from the Fred Hutchinson Cancer Research Center and collaborating institutions have uncovered how poxviruses evolve to rapidly adapt against host defenses despite their low mutation rates.

Poxviruses are a group of DNA-containing viruses such as smallpox. They are highly virulent and able to cross species barriers, yet their process of doing so is a mystery because they exhibit low mutation rates.

Smallpox was considered officially eradicated by the World Health Organization in 1980, though a renewed interest in its biology has come from concern about its use as a bioterrorism agent. The new research may help lead to the development of better antiviral strategies.

The discovery offers new insight into how large, double-stranded DNA viruses evade host immunity and become drug resistant. It offers particular insight into understanding how diseases may be transmitted to humans from animals.

The research will be released in the journal Cell by senior author Harmit S. Malik, a member of the Hutchinson Center's Basic Sciences Division, and first author Nels C. Elde, a former post-doctoral researcher in Malik's lab.

"Poxviruses encode a variety of genes that help them to counter host immune defenses and promote infection," Elde, now an assistant professor of human genetics at the University of Utah School of Medicine, said. "Despite ample evidence that the poxvirus genome can undergo adaptive changes to overcome evolving host defenses, we still don't know that much about the mechanisms involved in that adaptation."

The researchers used the vaccinia virus, the type of poxvirus used in the smallpox vaccine, in order to mimic viral adaptation and evolution as it occurs in nature. Previous research detailed how a host-defense protein called protein kinase R is a major hurdle to poxvirus infection. Poxviruses have evolved to encoded two genes, K3L and E3L, using them to stop host-defense mechanisms that usually prevent from poxvirus infection.

The vaccinia virus is altered to delete the E3L gene, evolving to successfully replicate the presence of human PKR, according to the research.

"Dramatically, serial propagation of this 'weaker' virus rapidly resulted in strains that became much more successful at replicating in human cells," Malik said.

Research showed that the virus quickly defeated PKR by selectively increasing the number of copies of the K3L gene in its genome. Malik said this adaptation is like the bellows of a musical according.

"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," Malik said.

The findings show that viruses that can quickly expand their genome have an immediate evolutionary advantage over those that cannot.

Additionally, the researchers saw 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."