Publication of flu study reveals full nature of threat

It's one of the most troubled scientific gestations on record. Nine months after it was first presented at a conference, research showing that just five mutations lead to a deadly H5N1 bird flu which transmits through the air between mammals has finally been published. Estimates published with it show that nature might well produce this virus too ? and reveal the science we now need to head off that threat.

The research, by Ron Fouchier and colleagues at Erasmus Medical Centre in Rotterdam, the Netherlands, was presented at a meeting and reported by New Scientist last September. But its publication ? and that of similar work by Yoshi Kawaoka at the University of Wisconsin-Madison ? was delayed by concerns that other labs would recreate airborne H5N1 with bioterrorist intent, or that insufficient containment might allow the virus to escape. In March, an advisory committee of the US agency which funded the work voted that these risks were outweighed by the benefits of publishing.

The main benefit was that it alerts us to some of the warning signs that might suggest one of the vast number of H5N1 viruses circulating in birds could become a pandemic. Now that both studies have been published, it is clear why they felt this would be a good idea.

Each lab did different things to H5N1 to make it transmissible. All but one of the five mutations that did the trick were different. Yet all did remarkably similar things to the virus. "Now we know what changes in the behaviour of the virus can make it transmissible, we can watch for any mutations with those effects ? not just our particular ones," says Fouchier.

For one thing, you need to change the HA surface protein so it binds a cell-surface sugar in mammals' noses, instead of the one it binds in birds. You also need a mutation in the RNA-replicating polymerase enzyme that adapts it to mammals' cooler bodies.

In both studies, further exposure of these viruses to ferrets, the best experimental mammal, induced further changes. Both viruses got rid of a sugar on the tip of HA. And both turned up a further, novel mutation. Kawaoka's stabilises the virus while attacking the cell. Fouchier's is at a spot in the HA protein where, he thinks, it may have similar effects.

Beyond the lab

Can this happen in nature? In a companion paper, Derek Smith and Colin Russell at the University of Cambridge, and colleagues, say all these mutations are already seen in bird flu ? although two of the three sugar-binding mutations were in H2 or H3 viruses, not H5N1.

The polymerase adaptation, meanwhile, occurs in nearly 30 per cent of H5N1 sequenced so far. The sugar loss occurs in more than half of sequences. Both stabilising mutations have been seen in Chinese H5N1.

Russell's team calculate that in many sequenced viruses containing some of the required mutations, only three to four single nucleotides in the viral DNA must mutate to get the rest they need to go airborne.

We don't know how fast the mutations accumulate. Using a mathematical model, however, Russell's team found that a virus that needs only three more mutations could well emerge within the five-day course of a single mammalian infection.

And it could be happening already. The virus you sneeze out is a cloud of slightly different mutants. The sequences on record for H5N1 are mostly "consensus" ? an average. The rest of the nucleotide changes required for H5N1 to go rogue might already be hiding within this consensus.

"We need to get those samples out of the freezer again and do some deep sequencing to see what minority mutations are there, and how often they appear," says Smith. We also need to establish just how deadly the transmissible viruses really are. For now, such research is blocked under a moratorium on work that boosts H5N1 virulence or transmission.

Journal references: The Fouchier paper Science, DOI: 10.1126/science.1213362; the Russell paper Science, DOI: 10.1126/science.1222526

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