H5N1 mutation that could help spark pandemic identified

Oct 5, 2007 (CIDRAP News) – An international research team led by the University of Wisconsin at Madison (UW-Madison) has identified a key mutation that would arm the H5N1 avian influenza virus with one of the tools it needs to more easily infect and spread among humans.

The mutation consists of a single amino acid change that improves the virus' ability to infect cells in the upper respiratory tract of mammals, according to a press release today from UW-Madison. The research group, headed by virologist Yoshihiro Kawaoka, published its findings today in the online journal Public Library of Science Pathogens (PLoS Pathogens).

The change promotes better viral replication at the lower temperatures found in the upper airways of mammals, the press release said. Once the H5N1 virus is established in the upper respiratory tract, infected patients can more easily spread the disease to others through coughing and sneezing, making the infection more contagious.

The authors write that the hemagglutinin protein's specificity for avian- or human-type receptors on airway cells is thought to be a major factor governing the efficient transmission of H5N1 viruses. Yet the disease still doesn't spread easily among humans, though scientists have isolated from humans some H5N1 viruses that had specificity for human receptors.

To determine what other amino acid substitutions are needed to make the virus more transmissible among humans, they explored the role of the amino acid at position 627 of the PB2 viral protein, one of the key proteins involved in viral replication. The scientists used two H5N1 viruses—one from the lungs and one from the upper airway—that were isolated from a single patient in Vietnam. They found that the virus from the patient's upper airway exhibited a single amino acid change at position 627 of PB2: from glutamic acid (Glu) to lysine (Lys).

The researchers then compared the growth of the two viral strains in mice and in different cell types. They found that viruses with Lys at position 627 replicated more efficiently in mammalian respiratory tracts, at temperatures as low as 33°C [91.4°F], and in a wider range of cells than those with Glu at the same amino acid position.

Kawaoka said in the UW-Madison press release that the H5N1 viruses circulating now are more "mammalian-like" than the ones that circulated in 1997, when the first human infections were identified.

"The viruses that are circulating in Africa and Europe are the ones closest to becoming a human virus," he said.

However, the researchers say in their report that additional genetic changes are probably needed to equip the H5N1 virus with full pandemic potential. "Indeed, multiple amino acid changes have been identified in the so-called Spanish influenza virus, which is thought to be derived from an avian antecedent," they write.

Kawaoka and his team believe it's only a matter of time before the H5N1 virus evolves into a strain that's capable of launching a pandemic, the UW-Madison release says.

"I don't like to scare the public, because they cannot do very much," Kawaoka was quoted as saying in a Reuters news report today. "But at the same time it is important to the scientific community to understand what is happening."

Michael T. Osterholm, PhD, MPH, said the Kawaoka group's findings are important for understanding the pandemic potential of H5N1. Given what is known about currently circulating H5N1 strains, the changes described in the study are of concern, said Osterholm, director of the University of Minnesota Center for Infectious Disease Research and Policy, which publishes CIDRAP News.

"The billion-dollar question is how many more changes are required and will H5N1 ever achieve this," he said. "We must plan as if it will."

Hatta M, Hatta Y, Kim J, et al. Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice. PLoS Pathogens 2007 Oct 4;3(10):e133[Full text]

See also:

Oct 5 University of Wisconsin press release

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