This drawing shows part of the atomic-level structure of coxsackievirus B3 polymerase, which is responsible for making copies of the virus genome. The researchers replaced the orange phenylalanine 364 that is found in two different positions, with the turquoise tryptophan that is larger and covers both positions without needing to move. This causes fewer mutations to be made and reduces the ability of the virus to replicate and cause disease. Credit: Olve Peersen/Colorado State University
A genetic modification to a type of coxsackievirus that strips its ability to replicate, mutate and cause illness. They hope their work could lead to a vaccine for this and other viruses like it. Peersen’s group seeks to understand the complex biochemical replication machinery of positive-sense ssRNA viruses, a group that includes coxsackievirus, poliovirus, dengue and Zika. For their most recent work, the team focused on coxsackievirus B3, which causes heart disease. (It is closely related to coxsackie A viruses, which cause hand, foot and mouth disease in children.) The viral RNA encodes for about a dozen proteins, one of which is the enzyme responsible for making new copies of the virus.
In earlier work, Peersen and co-authors had discovered the exact chemical steps by which RNA-dependent RNA polymerase copies the virus genome. The polymerase makes 3 of 4 random mistakes that allow the virus to continually evolve and survive.
The researchers have built upon this breakthrough to design a way to “outsmart Mother Nature,” Peersen said, by reengineering one key part of the polymerase enzyme so the virus can’t grow very rapidly in a cell. Their technology could lead to what’s called a live-attenuated vaccine. Such vaccines contain a weakened version of the virus, purposely injected to trigger the production of antibodies and create immunity rather than cause disease.
The classic live-attenuated vaccine is for poliovirus, invented by Jonas Salk in the mid 20th century. But the process isn’t foolproof. The simple RNA genome lets viruses make millions of copies within days, and many of those copies contain “mistakes,” or mutations, that can slightly alter the vaccine virus and restore its ability to cause disease. That’s one reason why RNA viruses are hard to eradicate and why some people get vaccine-induced sickness.
To minimize the chances of a vaccine-induced infection, the researchers changed one specific amino acid in the RNA polymerase (a phenylalanine) to another (tryptophan). First, they showed the tryptophan caused the polymerase to make fewer mutations, which reduced its ability to replicate and cause disease. Second, even if the virus tries to mutate the change away, then it can no longer replicate, so the virus self-destructs – and researchers call their modification a “genetic poison pill.”
The demonstration of this poison pill in the coxsackievirus B3 could theoretically translate to other positive-sense RNA viruses, including those linked to asthma and to foot-and-mouth disease, a major animal health concern in Europe and S. America. http://source.colostate.edu/biochemists-feed-poison-pill-to-deadly-virus-with-a-funny-name/
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