Friday, 11 January 2013

Reassortment among viruses (other than influenza!)
Want to read about reassortment in viruses? Sure you do. Look it up though and you'll more than likely be looking at a list dominated by influenzavirus. My guess is that in any virology course in the world influenzavirus is the example given when the topic of reassortment arises. Rightly so would be a fair argument; it's easy to relate to and is touted as the virus with the most potential to wreak havoc upon the human race. I've got nothing against influenza (scientifically), but there are many other viruses which undergo reassortment. 

If you don't already know, (and don't want to look it up), reassortment is a property of viruses with a segmented genome, and refers to the mixing of genomic segments when two or more viruses of the same species co-infect the same cell. Virus replication forms a pool of each of the virus segments such that, when it comes to the stage of forming a new virus particle, there is more than one option for each segment to make up the genome of the progeny virus. Virology blog covers it more in depth. In contrast to the accumulation of polymerase errors from copying the genome (genetic drift), reassortment (genetic shift) is a quick and simple way in which to evolve as a virus and generate increased genetic diversity. Over time with many rounds of reassortment it can become complicated - the following image is from the Nature paper describing the origin of each of the 8 segments of the H1N1 pandemic influenza strain.

Origin of the pandemic H1N1 swine influenza strain as a result of reassortment. From smith et al 2009.
Due to the complete switching of a segment of genetic code, reassortment can result in viruses with vastly altered properties, the most obvious of which is antigenicity. Say each virus had a different coloured coat, reassortment could allow a virus with a green coat to acquire a red coat. At first this might not seem much of an issue, but it can have major implications regarding vaccine efficacy - potentially allowing a virus to re-enter    a population. We published a paper recently on Bluetongue virus which included a virus found in a cow in France which was primarily of BTV-8 origin (and the characteristics this imparts), but to the immune system appeared to be BTV-1. At this point farmers were vaccinating against BTV-8 so in theory this virus, carrying genetic information of a virus successfully controlled by vaccination, could infect the vaccinated animals. BTV has 26 such 'types', and there are probably more. We engineered viruses to see whether we could work out whether segments from one virus or the other imparted specific characteristics, but (frustratingly) there wasn't really anything different between the viruses in the characteristics we looked at, apart from the difference in serotype associated with a specific protein.

FRA2008/24 is a reassortant bluetongue virus, comprising a core of BTV-8 (green) with the serotype determining protein of BTV-1 (blue) from Shaw et al 2013

A group in the Netherlands has also done this kind of work, either by adding their own segments to a replicating virus and looking for a virus which has incorporated their engineered segment or, like us, completely engineering the virus from scratch. Both approaches allowed them to make reassortant viruses in the lab. In the latter case, they were able to swap the gene responsible for the serotype of an avirulent virus (BTV-6), with that of BTV-8 (very virulent), resulting in a virus which, to the immune system appeared to be BTV-8, but had all the attenuated characteristics of the the parent virus. This is essentially a live attenuated vaccine; similar to the Sabin polio vaccine, or Plowright's Rinderpest vaccine used during the (successful) eradication programme.

Clearly, reassortment can be massively massively beneficial. On the other hand, would you use that virus in the face of a Bluetongue outbreak? Reassortment is again the issue; there would be the potential to generate never before seen viruses with unknown clinical outcomes if a wild type virus infected an animal during the time the vaccine virus was replicating. The haemorrhagic Ngari virus within the family Bunyaviridae provides a stark example whereby the viruses from which it is formed (a combination of Batai and Bunyamwera) are both relatively innocuous. Vaccinating sufficiently ahead of time or during winter in the absence of transmission would be possible ways around it, but a better scenario is to make non-reassortantable bluetongue viruses based upon attenuated strains such as the BTV-6 used by the Dutch group.

Tracking reassortable viruses in the field becomes a problem too. The more people look by full genome sequencing, the more reassortants they find; if there are sufficient variants, reassortment may actually be the norm as opposed to the exception. This creates headaches when it comes to phylodynamics and tracing the viruses, as I mentioned in a post about equine influenza. Full genome sequencing is again likely to come to the rescue, and there has been another paper recently providing a method for the detection of reassortant viruses in phylogenies; guess what, it's about influenza.....

van Gennip, R., van de Water, S., Maris-Veldhuis, M., & van Rijn, P. (2012). Bluetongue Viruses Based on Modified-Live Vaccine Serotype 6 with Exchanged Outer Shell Proteins Confer Full Protection in Sheep against Virulent BTV8 PLoS ONE, 7 (9) DOI: 10.1371/journal.pone.0044619

Smith, G., Vijaykrishna, D., Bahl, J., Lycett, S., Worobey, M., Pybus, O., Ma, S., Cheung, C., Raghwani, J., Bhatt, S., Peiris, J., Guan, Y., & Rambaut, A. (2009). Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic Nature, 459 (7250), 1122-1125 DOI: 10.1038/nature08182

Shaw, A., Ratinier, M., Nunes, S., Nomikou, K., Caporale, M., Golder, M., Allan, K., Hamers, C., Hudelet, P., Zientara, S., Breard, E., Mertens, P., & Palmarini, M. (2012). Reassortment between Two Serologically Unrelated Bluetongue Virus Strains Is Flexible and Can Involve any Genome Segment Journal of Virology, 87 (1), 543-557 DOI: 10.1128/JVI.02266-12

van Gennip, R., Veldman, D., van de Water, S., & van Rijn, P. (2010). Genetic modification of Bluetongue virus by uptake of "synthetic" genome segments Virology Journal, 7 (1) DOI: 10.1186/1743-422X-7-261

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