Scientists recreate 1918 flu virus, see parallels with H5N1

Oct 5, 2005 (CIDRAP News) – Scientists today reported findings that may help explain what made the 1918 pandemic influenza virus so deadly and that reveal similarities between that virus and the H5N1 avian influenza virus now circulating in Asia.

Scientists at the Centers for Disease Control and Prevention (CDC) reconstructed the virus and tested it in laboratory animals, which quickly died. The CDC says the work, to be reported in Science, will enhance preparedness for the next flu pandemic, a potential benefit believed to justify the risk of recreating the virus and publishing the information.

In the other study, researchers at the Armed Forces Institute of Pathology (AFIP) report that the close resemblance of the 1918 virus to avian flu viruses suggests that the 1918 virus was an avian strain that managed to adapt to humans without first acquiring any genes from existing human flu viruses. Further, the researchers found that several of the same mutations that differentiated the 1918 virus from avian flu viruses are found in the H5N1 virus, which has killed more than 60 people in Asia. The report appears in Nature.

The 1918 flu pandemic, regarded as the worst in history, killed as many as 100 million people. In recent years scientists have been able to learn the structure of the H1N1 virus that caused it by analyzing samples preserved from pandemic victims, including tissue from a frozen body exhumed in Alaska and material stored in the AFIP's warehouse of autopsy samples.

In a joint statement today, the directors of the CDC and the National Institute of Allergy and Infectious Disease (NIAID), Dr. Julie Gerberding and Dr. Anthony Fauci, said, "For the first time, researchers have deciphered the entire gene sequence of the 1918 virus and have used sophisticated techniques to assemble viruses that bear some or all of these genes so their effects can be understood.

"Importantly, they have identified gene sequences that may predict when an influenza virus strain is likely to spread among humans. They also have determined in the test tube and in mice which genes are most likely to account for the lethal effects of the 1918 virus." The statement was released by the NIAID.

"The new studies could have an immediate impact by helping scientists focus on detecting changes in the evolving H5N1 virus that might make widespread transmission among humans more likely," the statement said.

Because of concern that terrorists could exploit the information, both articles were reviewed by the National Science Advisory Board for Biosecurity before publication, according to the NIAID statement. The board unanimously endorsed publishing them.

"The rationale for publishing the results and making them widely available to the scientific community is to encourage additional research at a time when we desperately need to engage the scientific community and accelerate our ability to prevent pandemic influenza," Gerberding and Fauci stated.

Resurrection of the 1918 virus
In the Science article, Terrence M. Tumpey and colleagues report that they generated a flu virus bearing all eight gene segments of the 1918 virus in order to study what made it so virulent. They exposed groups of mice to that virus and to other viruses in which some of the 1918 virus's genes were replaced by genes from recent flu viruses.

The 1918 virus turned out to be extremely virulent. Mice infected with it died in as little as 3 days, and mice that survived as long as 4 days had 39,000 times as many virus particles in their lungs as did mice infected with a control flu virus, a Texas strain of H1N1 from 1991. All the mice infected with the 1918 virus died, while those exposed to the Texas strain survived. Further, the 1918 virus was at least 100 times as lethal as an engineered virus that contained five 1918 genes and three genes from the Texas H1N1 strain.

The researchers found that the mice had severe inflammation in their lungs and bronchial passages—findings very similar to those in people who died of the 1918 virus. However, the virus did not spread in the mice to the brain, heart, liver, or spleen.

The scientists also tested the virus's behavior in a laboratory culture of human lung cells. Within 24 hours, the lung cells released at least 50 times as much virus as did lung cells infected with the Texas H1N1 strain.

In comparing the 1918 virus with recombinant viruses containing only some of the 1918 genes, the researchers found that the 1918 hemagglutinin and polymerase genes were "essential for optimal virulence." The complete 1918 virus was more pathogenic for mice than any other human flu virus that has been tested, the report says.

Likeness between 1918 virus and avian strains
The Nature article, by Jeffery Taubenberger and colleagues from the AFIP, reports on an analysis of the three polymerase genes in the 1918 virus, the last three genes to be fully spelled out. The researchers found that these genes closely resembled their counterparts in avian flu viruses.

"The polymerase protein sequences from the 1918 human influenza virus differ from avian consensus sequences at only a small number of amino acids, consistent with the hypothesis that they were derived from an avian source shortly before the pandemic," the report states.

Accordingly, the researchers propose that the 1918 virus was not a "reassortant," like those that caused the smaller pandemics of 1957 and 1968. In those cases, avian flu viruses traded some genes with human-adapted flu viruses to spawn new hybrids. The 1918 virus was "an entirely avian-like virus" that somehow adapted to humans, they suggest.

The report says only 10 amino-acid changes in the polymerase genes consistently distinguish the 1918 virus and subsequent human flu viruses from the same genes in avian viruses. It adds, "A number of the same changes have been found in recently circulating, highly pathogenic H5N1 viruses that have caused illness and death in humans and are feared to be the precursors of a new influenza pandemic."

A news story accompanying the report in Nature says that all eight genes from the 1918 virus differ in important ways from other human flu genes, which suggests that none of the genes came from a flu strain that had previously infected people. "It is the most bird-like of all mammalian flu viruses," Taubenberger is quoted as saying.

According to the Nature news story, some scientists are questioning the wisdom of recreating the 1918 virus and publishing information on how it was done. Richard Ebright, a bacteriologist at Rutgers University in New Jersey, said Tumpey and colleagues "have constructed, and provided procedures for others to construct, a virus that represents perhaps the most effective bioweapons agent now known."

In a news release, the CDC said it used "stringent" precautions in the research. "The work was done in a high-containment Biosafety Level 3 lab with enhancements that include special provisions to protect both laboratory workers and the public from exposure to the virus," the agency said.

Taubenberger JK, Reid AH, Lourens RM, et al. Characterization of the 1918 influenza virus polymerase genes. (Letter) Nature 2005 Oct 6;437(7060):889-892 [Full text]

Tumpey TM, Basler CF, Aguilar PV, et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 2005 Oct 7;310(5745):77-80 [Abstract]

See also:
Oct 5 CDC Press release
http://www.cdc.gov/media/pressrel/r051005.htm

Oct 5 NIAID Press release
http://www.niaid.nih.gov/news/newsreleases/2005/Pages/0510state.aspx

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