|Chikungunya virus particles emerging from an infected cell - is genetic diversity important to this virus?|
At around 1 mutation per 1,000 - 100,000 nucleotides per round of replication, RNA viruses have the highest mutation rate of anything seen in nature to date. During an infection of a single cell, thousands of new genomes are produced that will go on to make new virus particles; each genome will differ from another at most maybe 10 nucleotides (given an average virus of 10 kilobases in length).
This activity results in a 'swarm' of genome sequences that continuously sample sequence space and form what is known as a quasispecies, allowing the virus to adapt to it's complex environment; due to their general lack of proof-reading capability, large population sizes and mode of replication, these RNA viruses have an enormous bank of genetic diversity at their disposal. All those genome sequences uploaded to the public databases represent an average of the thousands of sequences isolated and fail to recognize their true diversity. But how important is it during an infection? No one has really been able to say, that is until now. And it turns out to be very important indeed and may even allow us to produce rationally attenuated vaccines for many of the worst viral pathogens.
According to a recent paper published in PNAS this week, this ability to produce quasispecies populations has a major effect on the outcomes of a viral infection. The team - led by Marco Vignuzzi of the Pasteur Institute in Paris - isolated a mutant Chikungunya virus (small positive-sense RNA virus) that wasn't all that good at mutating when compared to a wild-type one. They took the two variants: the more diverse versus less diverse and looked at how well it grew in mosquitoes and mice, representing its natural host species. While no significant differences were seen between the two viruses in cell culture, in vivo, the high-fidelity virus grew to lower levels than the wild-type, suggesting that there is a fitness cost associated with replicating more accurately during an infection.
This phenomenon had previously been documented with poliovirus (here and here), which is another small, positive-sense RNA virus, but as it was looked at in a rather unnatural model (polio receptor transgenic mice) it's general applicability wasn't known. This paper published now, clearly shows that this original observation can be applied to other RNA viruses and is relevant in a more natural model. Yet none of the papers have truly assessed why this occurring but it appears (mostly hypothetical) to be stemming from either the ability to revert deleterious mutations back to an advantageous one or possibly through generating co-operative genomes, each one successful at a different aspect of an infection (see review here). The use of this chikungunya virus model will most likely uncover some of the reasons why this is happening.
As one of the original poliovirus papers hypothesizes:
...certain variants within the population might facilitate the colonization of the gut, another set of mutants might serve as immunological decoys that trick the immune system, and yet another sub-population might facilitate crossing the blood–brain barrier.
Taken together, our data support a central concept in quasispecies theory, namely that successful colonization of an ecosystem (in this instance, an infected mouse) occurs by cooperation of different virus variants that occupy distinct regions of the population sequence distribution
It all makes me wonder how generally this observation could be applied to other RNA viruses, especially as many other viruses have been shown to form - at least heterogeneous - populations that have been linked to how well they cause disease and are transmitted.
Coffey, L., Beeharry, Y., Borderia, A., Blanc, H., & Vignuzzi, M. (2011). Arbovirus high fidelity variant loses fitness in mosquitoes and mice Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1111650108