Changes Cited in Bird Flu Virus

"It is an amazing feat," said Edwin D. Kilbourne, 85, one of the country's leading influenza virologists and a retired professor from Mount Sinai School of Medicine and New York Medical College. "It's a tribute to imagination, perseverance and a great deal of very hard work."

The reconstruction of the 1918 virus is expected to provide immediately useful insights to epidemiologists studying the kind of flu viruses that are being passed among dozens of species of birds and mammals worldwide.

"I think we have been able to unmask the 1918 virus, and it is revealing some of the secrets that will help us prepare for the next pandemic," said Julie L. Gerberding, director of the CDC.

By identifying how the 1918 virus differs genetically from related viruses that do not infect people, researchers hope to pinpoint the mutations an animal flu virus needs to acquire to adapt to human beings. Taubenberger estimates, as a rough guess, that 25 mutations may be essential.

"It could theoretically provide a checklist for surveillance," he said. "You might be able to say: This strain has six of these changes; it's a worrisome virus we need to keep our eye on. Or this one has none."

It will be especially useful to compare the 1918 gene sequence to those of the two flu viruses that have caused pandemics since then -- the "Asian flu" of 1957 and the "Hong Kong flu" of 1968. Hybrid viruses containing genetic features of each can then be constructed and studied in the laboratory.

"We are trying to elucidate the general rules of human adaptation. How does a bird virus become a human virus? Generically put, that is what we're trying to answer," Taubenberger said.

In their paper, Taubenberger, Ann. H. Reid, Thomas G. Fanning and other colleagues at the AFIP describe three genes that make up more than half the 1918 virus's genetic material. Previous papers had described the reconstruction of the virus's five other genes.

Analysis of all eight genes strongly suggests that the Spanish flu virus descended directly from a bird virus and moved into human hosts after slowly accumulating the necessary mutations. It does not appear to have combined with a pig or human flu virus in a process called "reassortment" and to have become a human virus in a sudden step. The 1957 and the 1968 pandemic strains arose through reassortment.

This insight hints that H5N1 might also be capable of adapting to human beings through gradual evolution. In fact, there is evidence the process is already underway.

The polymerase genes described in the new paper produce three proteins that together allow the virus to replicate in cells. Of the 2,232 amino acids in those proteins, 10 are consistently different in the 1918 virus and in other human flu viruses, compared with the proteins in avian flu viruses. The researchers believe the 10 changes may be keys to enabling avian viruses to replicate easily in people. In the past two years, scientists have isolated H5N1 viruses in Asia that have two of the 10 changes.

Similarly, the researchers believe adaptation to humans requires six changes in another gene, called nucleoprotein. H5N1 strains have been found carrying one. In yet another gene -- for a protein called matrix -- four changes appear necessary. Surveillance has turned up H5N1 strains carrying two of the four.

Altogether, the changes suggest that though H5N1 is still a bird virus, it is partway along a path to becoming a human virus.

In a second paper to be published tomorrow in Science, Terrence M. Tumpey of the CDC and Adolfo Garcia-Sastre of Mount Sinai describe experiments with the live, reassembled virus.

They found that mice infected with the microbe died in three days -- unusually fast -- and that unlike most flu viruses, the 1918 strain replicated deep in the lung, not just in the throat and bronchi. That fits the observation that many victims of Spanish flu died when blood or fluid flooded their lungs, often after only a day or two of illness.

The gene sequence of the 1918 virus is now public, which theoretically means it could be reconstructed by others. Publication of the new papers was approved by the federal body that reviews research that could have bioterrorism uses, the National Science Advisory Board for Biosecurity.

Many scientists, however, doubt that Spanish flu could cause a pandemic today if it got out of the laboratory. That is because virtually everyone on Earth has been exposed to many of its descendants in the H1N1 flu virus family -- and consequently are at least partly immune to it.