When influenza viruses with different genetic make-up co-infect a cell there is the possibility that they will mix their genetic endowments. The influenza virus is designed to do only one thing: make a copy of itself. It does this by tricking the host’s protein manufacturing machinery to use the virus’s genetic blueprint to make a viral copy. Influenza genes come in eight discrete packages and at some point these genetic segments are naked in the cell. If the segments of two viruses are in the cell at the same time the segments can mix and match, with some of the segments of one virus being packaged in the progeny viruses with segments from the other virus. This is called reassortment of gene segments. It is a major mechanism of genetic variation in flu viruses. Two of the segments have coding regions for two proteins in the outer protein coat of the virus, hemagglutinin and neuraminidase. There are 16 different major versions (subtypes) of the hemagglutinin protein (each with lots of strain variation) and 9 neuraminidase subtypes. The hemagglutinin subtypes are numbered 1 to 16 and neuraminidase subtypes 1 to 9. The only subtypes that normally infect humans are H1, H2 and H3 and N1 and N2. Today the seasonal flu viruses are either H1N1 or H3N2. But evidence has been emerging for a few years that the actual situation is much more complex because there are 6 other gene segments and they also reassort. A paper from the Holmes group at Penn State and their collaborators has started to fill some of the details:
Researchers who conducted genetic analyses of hundreds of influenza viruses collected during the 2006-07 flu season found that many different variants circulated in the US at the same time, suggesting that the way each year’s epidemic spreads is more complicated than previously suspected.
The scientists, led by Martha I. Nelson of Pennsylvania State University as first author, found that several different clades, or lineages, of influenza A subtypes H1N1 and H3N2 circulated at the same time and even in the same localities, according to the report in PLoS Pathogens.
“Overall, the co-circulation of multiple viral clades during the 2006-2007 epidemic season revealed patterns of spatial spread that are far more complex than observed previously, and suggests a major role for both migration and reassortment in shaping the epidemiological dynamics of human influenza A virus,” the report states. It says the findings indicate that several viral strains were introduced separately into the country.
Among other things, the authors found that clades of the same subtype (H1N1 or H3N2) exchanged genetic material through reassortment in a number of instances. In one case, this gave rise to an H3N2 variant that was sensitive to the antiviral drugs amantadine and rimantadine, unlike most H3N2 strains in recent years. (Robert Roos, CIDRAP News)
There were nearly 300 isolates from a season that was dominated by H1N1, but this subtype (H1N1) was present in 8 different variants or lineages, representing different combinations of the other gene segments. There was much less variation in the H3N2 subtype that year (only two lineages). The same location always had more than variant (whenever the location had more than one isolate), so all sorts of variations of influenza virus are circulating simultaneously, sometimes in the same infected person. Houston, Texas, had six different lineages of H1N1 circulating at once.
Is there a pattern in the spread of the different variants? If there is, it isn’t evident at this point:
“Rather than a single viral lineage spreading across the US, multiple lineages of both A/H3N2 and A/H1N1 influenza virus were separately introduced and co-circulated, allowing for reassortment within subtypes and greatly complicating patterns of spatial-temporal spread,” the report states. “Given the extent of genetic diversity observed during this season, obtaining a strong signal for the spatial-temporal pattern of spread of multiple different lineages clearly would entail a large increase in sampling.” (quoted from Nelson MI, Edelman L, Spiro DJ, et al. Molecular epidemiology of A/H3N2 and AH1N1 influenza viruses during a single epidemic season in the United States, PLoS Pathogens 2008;4(8))
We shouldn’t be surprised at this. If the H and N segments reassort so do the others, and they aren’t “seen” as easily (or at all) by the immune system. It is only recently we have had the ability to analyze the full complement of genetic detail in hundreds of related isolates. Along with this new information will have to come new ways of mathematical analysis, an absolute necessity if we are to make sense of the fire hose quantity of raw data being produced by these techniques.
Lots to do and technically difficult.