How are new viruses made?

I'm sure you are all familiar with H1N1, the influenza strain that emerged in 2009 and which contained genetic elements from four different strains: two swine flu strains, one avian flu strain, and one human flu strain.

How did this incredible mix-up happen?

One thing I've learned in the five years I've spent studying viruses is that these little things are genetic brewing machines (I just made that expression up, please don't quote me!). They can carry genetic material from different organisms, they can integrate in the host's genome, they can transport genetic material from one organism to another. The viral genome of a flu virus in particular is split in different portions called segments. Now suppose an avian flu virus and a swine flu virus infect the same hosts, and two viral particles coinfect the same cell inside the host. Yes, you've guessed it: the genetic segments from the two distinct viruses can indeed "reshuffle" and create a completely new virus. In the case of H1N1, this pattern of coinfection and "reshuffling" (called segment reassortment) happened more than once and across three different hosts: birds, pigs, and humans.

Reassortment of segmented viruses happens when two genetically distinct viral species coinfect the same cell and exchange genomic segments, a mechanism that ensures rapid novel virus creation. In the past, novel influenza strains have appeared when the virus's genomic segments reasserted with non-human flu genomic segments. The host's immune system may be prepared to recognize either strain but not a combination of both, hence the new virus can, potentially, evade adaptive immunity.

An interesting bit of the puzzle is that this reassortment does not appear to be random: there is a "reassortment bias", in other words, not all possible "reshufflings" of the genomic segments are equally likely to happen. There are constraints in terms of the genetic information that needs to be exchanged across the segments in order to make a new virus. The ability to predict which reassortments are most likely can help us be prepared for future outbreaks like H1N1.

In a recent PNAS paper [1], Greenbaum et al. use the mathematical framework of information theory to infer the viral populations produced by a coinfection out of the possible repertoire of progeny viruses. They look at quantities like entropy and mutual information to measure the genetic variation, predict which segments share relevant genetic information, and derive general segregation rules of how reassortment may happen.

"We study, for influenza and other segmented viruses, the extent to which a virus’s segments can communicate strain information across an infection and among one another. Our approach goes beyond previous association studies and quantifies how much the diversity of emerging strains is altered by patterns in reassortment, whether biases are consistent across multiple strains and cell types, and if significant information is shared among more than two segments. [1]"

Mutual information gives an upper bound on how much information strains can exchange. Pushing the rate of reassortment past this bound would disrupt viral segment communication and stop the creation of new virus. This is something I've heard about viral mutation rates, as well. Rapid turnover in genetic diversity is an advantage for tiny organisms like viruses and bacteria because it allows them to quickly develop escapes to the immune system: it's the Red Queen Effect I've talked about in the previous post. However, if this turnover it's too quick you get the opposite effect: when you go past the limit and start accumulating too much diversity, the population rapidly goes extinct because deleterious mutations happen more frequently than advantageous ones. This suggests that tweaking the diversity increase beyond this limit may be a novel defense strategy.

"Understanding how much these segments transfer information about their strain of origin, and to what extent this is possible, can ultimately lead to novel antiviral strategies."

Greenbaum, B., Li, O., Poon, L., Levine, A., & Rabadan, R. (2012). From the Cover: Viral reassortment as an information exchange between viral segments Proceedings of the National Academy of Sciences, 109 (9), 3341-3346 DOI: 10.1073/pnas.1113300109