Viruses that have two of these mutations are already common in birds, meaning that there are viruses that might have to acquire only three additional mutations in a human to become airborne transmissible."—Colin Russell
It might be possible for human-to-human airborne transmissible avian H5N1 influenza viruses to evolve in nature, new research has found.
Currently, avian H5N1 influenza, also known as bird flu, can be transmitted from birds to humans, but not (or only very rarely) from human to human. However, two recent papers by Herfst, Fouchier and colleagues in Science and Imai, Kawaoka and colleagues in Nature reveal that potentially with as few as five mutations (amino acid substitutions), or four mutations plus reassortment, avian H5N1 can become airborne transmissible between mammals, and thus potentially among humans. However, until now, it was not known whether these mutations might evolve in nature.
The Cambridge researchers first analysed all of the surveillance data available on avian H5N1 influenza viruses from the last 15 years, focusing on birds and humans. They discovered that two of the five mutations seen in the experimental viruses (from the Fouchier and Kawaoka labs) had occurred in numerous existing avian flu strains. Additionally, they found that a number of the viruses had both of the mutations.
Colin Russell, Royal Society University Research Fellow at the University of Cambridge, said: "Viruses that have two of these mutations are already common in birds, meaning that there are viruses that might have to acquire only three additional mutations in a human to become airborne transmissible. The next key question is ’is three a lot, or a little?’ "
The scientists explored this key question using a mathematical model of how viruses replicate and evolve within a mammalian host and assessed the influence of various factors on whether the remaining three mutations could evolve in a single host or in a short chain of transmission between hosts
The factors that increased the likelihood of mutations evolving are:
1. Random mutation. The replication mechanisms of influenza viruses don’t make perfect copies. On average, every time an influenza virus replicates itself it makes approximately one mutation somewhere in the genome of each new virus. In each infected human there will be billions of viruses, and thus with many viruses replicating, multiple mutations can accumulate within a single host.
2. Positive selection. If some of the remaining mutations help the avian virus to adapt to mammals, then those mutations will make the viruses more fit and thus will be positively selected and preferentially accumulate.
3. Long infection. The longer someone is infected and producing new viruses, the more time there is for mutations to accumulate.
4. Functionally equivalent substitutions. The sets of substitutions identified by Fouchier and Kawaoka are unlikely to be the only combinations of substitutions capable of producing an aerosol transmissible virus. The probability of emergence increases with the number of combinations.
5. Diversity in the within-bird virus population. Given all of the mutations there are likely to be within a host due to random mutation, it is possible that the viruses from a bird that infect a human might have a mutation that would not be detected by routine surveillance. For example, if 100 virus particles from a bird infect a human and one of those particles had a key mutation, it would increase the probability of the mutation reaching high levels within a host even though routine sequencing would not detect it.