Just a few mutations away

With the world overcoming the initial pangs over swine flu (H1N1) outbreak, new questions have come up on the Mexican H1N1 virus’ damaging potential.
Scientists are wondering whether the H1N1 virus or even the H5N1 virus that caused bird flu can trigger a pandemic similar to the 1918,1957 and 1968 events. Should the world be prepared for such a catastrophe?
An early hint has come from US researchers who suggest that potential for a bird flu virus to cause a human flu pandemic is greater than previously thought.
They also illustrated how the current swine flu virus possibly modifies itself to spread through three continents within weeks affecting 1200 and killing 30 people.
Avian flu viruses can infect humans who have contact with birds. But these viruses tend not to transmit easily among humans.
In research published in the Proceedings of the National Academy of Sciences, Daniel Perez from the University of Maryland showed that after re-assortment with a human influenza virus, a process that usually takes place in intermediary species like pigs, an avian flu virus requires relatively few mutations to spread rapidly between mammals by respiratory droplets.

How the swine flu must have formed...

“This is similar to the method by which the current swine influenza strain is likely to have formed,” said Perez. The virus formed when avian, swine, and human-like viruses combined in a pig to make a new virus. The mutation allows spreading by respiratory droplets and infects humans. The virus is now spreading among human beings by sneezing and coughing.
In his study, Perez used avian H9N2 influenza virus, one that is on the list of candidates for human pandemic potential.
Using reverse genetics, a technique whereby individual genes from viruses are separated, selected, and put back together, Perez and his team created a hybrid human-avian virus.
Their hybrid has human flu genes internally and avian flu genes from the H9N2 virus on the surface. Though it comes from a different strain of avian flu from the one that contributed to the hybrid virus now causing the swine flu outbreak, Perez’s research virus is similar in origin to the swine flu virus because both involved a combination of avian and human influenza viruses.

Mutation

Perez infected ferrets (a small animal) with the virus and allowed the virus to mutate in the species. Before long, healthy ferrets that shared air space but not physical space with the infected ferret had the virus, showing that the virus had mutated to spread by respiratory droplets.
When the genetic sequences of the mutant virus and hybrid virus were compared, the only differences were five amino acid mutations, three on the surface, and two internally.
Two of the surface mutations were determined to be solely responsible for supporting respiratory droplet transmission.
Because so few mutations were necessary to make the hybrid H9N2 transmissible this way, they concluded that after an animal-human hybrid influenza virus forms in nature, a human pandemic of this virus is potentially just a few mutations away. But it’s not known at the moment whether there were similar natural re-assortments in the 1950s or 1960s which made the 1957 or the 1968 flu so deadly. Both were of avian origin but killed hundreds of thousands all over the world.
“It will be difficult to say because the parental avian flu viruses that gave rise to the 1957 and 1968 are not known,” Perez told Deccan Herald.
The Maryland professor found one of the two mutations in his lab strain that enabled respiratory transmission between mammals was on the tip of the HA surface protein – one of the sites where human antibodies created in response to current vaccines would bind.
“Because the binding site of the mutant virus is different from the virus upon which the vaccine is modelled, it may mean that current vaccine stocks would not be as effective against the H9N2 mutant strain as previously anticipated,” said Perez.
“We should keep this in mind when designing vaccines for an avian flu pandemic in humans,” he said. For the record, there is no commercial vaccine against H5N1 till now though several efforts are underway.

Potential of the virus

Asked about the damaging potential of the hybrid virus he created in the laboratory, Perez said, “We can only speculate that the pandemic potential could be similar, but there is nothing is our studies that would suggest that what we created in the lab is more dangerous than what already exists in nature.” However, scientists cannot predict whether these mutations are similar to the mutations in the current H1N1 outbreak.
“We do not know if the mutations we saw in the lab are the same that have made the H1N1 swine flu transmissible by respiratory droplets,” Perez said.  
“This is just the tip of the iceberg. Many more studies have to be done to see which combinations of mutations cause this type of transmission before we can design the appropriate vaccines,” he added.