AsianScientist (Sep. 10, 2014) – Scientists have demonstrated that the influenza A virus makes use of its error-prone genetic replication to increase diversity, thereby facilitating viral survival under different selection pressures. This research has been published in Nature Communications.
“Influenza virus relies on its own enzymes (RNA polymerase) to copy its genetic information during multiplication. The RNA polymerase is error-prone and makes random errors (mutations) during genome replication,” explained lead author Dr. Yen Hui-ling, assistant professor of School of Public Health at the University of Hong Kong (HKU).
Replication errors lead to the generation of a progeny viral population with minor genetic differences from each other. This genetic diversity is also termed “quasispecies” and it is believed to be an important strategy for RNA viruses to survive under selection pressures, such as host immune responses. However, it has been challenging to provide experimental proof for the role of “quasispecies” in RNA virus survival. This concept was first experimentally demonstrated using poliovirus but has not been studied for influenza virus to date.
“The outcome is the generation of a ‘swarm’ of virus mutants with minor genetic differences from each other. This genetic diversity facilitates influenza virus survival under different selection pressures. We generated influenza A viruses with increased RNA polymerase fidelity which allow us to study the role of genetic diversity experimentally,” Prof. Yen said.
Prof. Yen and her team generated the high fidelity influenza virus by passaging a human seasonal H3N2 influenza virus in the presence of ribavirin, a nucleoside analog that possess mutagen effect by increasing the error rate of influenza viral RNA polymerase. A single PB1-V43I mutation was identified to increase viral RNA polymerase fidelity in both seasonal H3N2 and highly pathogenic H5N1 influenza viruses.
The H5N1 virus with increased RNA polymerase fidelity multiplied efficiently in the mouse lungs. However, a decreased viral genetic diversity was noted and the mortality rate of mice infected by this mutant was found to be ten times less than the control. The study provided direct experimental evidence to demonstrate the role of viral genetic diversity in influenza virulence.
“This work leads to a different understanding of the mechanisms of virus virulence,” said co-corresponding author Professor Malik Peiris, who is the Tam Wah-Ching Professor in Medical Science at HKU.
“A single mutation in one of the influenza polymerase genes (PB1) can lead to decreased genetic diversity and populations of such viruses have reduced disease severity even though they appear genetically identical in all other respects when using conventional genetic sequencing methods. This was true for both seasonal influenza and highly pathogenic H5N1 influenza virus. This information provides a target for future development of antiviral drugs and an approach to improve live attenuated influenza vaccines,” he said.
The article can be found at: Cheung et al. (2014) Generation and Characterization of Influenza A Viruses with Altered Polymerase Fidelity.
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Source: University of Hong Kong.
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