Just hanging about

​ A single point mutation is enough to switch parainfluenza virus between acute and persistent.

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Presumably the question you are asking yourself is what determines persistence in acute RNA viruses? If not, why not?

Viruses have been shown to persist – stay present in the body, potentially after the symptoms of infection have passed. Most of the evidence and mechanism for viral persistence has been collected for DNA viruses and retroviruses (that is RNA viruses that convert their RNA genome into DNA and insert it into the host). However, there is clear evidence that non-retroviral RNA viruses can persist (see the review here). We normally think of these acute RNA viral infections as being short lived, cleared by the host and only succeeding if they can transmit to a new individual. However, this strategy has limitations, particularly if there are no new individuals who haven’t been infected by the virus. Therefore, viruses need to have evolved a way to maintain a reservoir, this is particularly important when we consider that viruses are obligate parasites – they have to use host cells to replicate and survive. It is particularly interesting to think that the viruses can persist in spite of selective pressure from the host immune response which is trying to clear the virus.

The question we set out to answer in a recently published study, led by Prof Rick Randall and Prof Steve Goodbourn, was how RNA viruses can switch between an acute and persistent state. The work focused on parainfluenza virus (PIV), which is a member of the paramyxovirus family. Viruses require specific proteins to make copies of their genetic information, which is described as the polymerase complex. The imaginatively named P protein of parainfluenza virus is a core part of the viral polymerase. If the P protein was phosphorylated (a mechanism by which cells can control protein activity), then the virus no longer replicated in the cells, but and this is important, the viral RNA was maintained within the cell. We then demonstrated that the phosphorylation status of the P protein and was determined by a single amino acid within the protein, if this changed then the protein could be activated or de-activated. Since amino acids are determined by the genetic code of the virus, specifically by 3 nucleotides, a single nucleotide change can alter the amino acid sequence, in turn affecting the phosphorylation of the protein and whether it is active or not. So in essence there is a switch that can control whether the virus makes copies of itself within the cell, given that RNA viruses have leaky polymerases (they make inaccurate copies of their own genes), this flip between active and inactive states can occur readily during the infection/ replication cycle. The switch may be driven by immune pressures, we demonstrated that lytic viral variants replicated to higher levels in a mouse model but were cleared much faster, whereas the persistent variant led to a prolonged infection. We proposed that the virus may start in an active state producing lots of copies of itself, before switching to a persistent state to develop a reservoir.

This was in essence a piece of basic research addressing a fundamental question in virology, but it does have broader impact, understanding why and how RNA viruses persist has implications for infection epidemiology as well as potential for developing novel vaccine platforms. 

Go to the profile of John Tregoning

John Tregoning

Reader in Respiratory Infections, Imperial College London

I have studied the immune responses to vaccination and respiratory infection for 15 years and have been an independent PI for 10 years. My group’s research program is focussed on prevention of respiratory infections. This research has focused on vaccines to a range of respiratory pathogens.

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