A team of Swiss investigators has found a new mechanism that is critical to the ability of certain avian influenza A viruses to infect humans. The mechanism overcomes a defense that normally protects human cells from infection by avian influenza. The research appeared in the Journal of Virology, a publication of the American Society for Microbiology. “Our data add another piece to the puzzle of how avian adapted viruses managed to replicate in human hosts,” said corresponding author Mirco Schmolke, PhD, professor of microbiology, Department of Microbiology and Molecular Medicine, University of Geneva, Switzerland. This ability to cross the species barrier is important because “highly pathogenic avian influenza A viruses pose a continuing threat to human and animal health and bear the potential for new influenza pandemics,” the researchers wrote. “Since 2003, 860 confirmed cases of human H5N1 IAV have been reported to the World Health Organization, with an estimated mortality rate of about 50%.” So far, however, no human-to-human transmission of this virus has been reported. Normally, to protect human cells from viruses, a human cellular defense mechanism, called a “restriction factor,” grabs hold of a piece of the virus’ replication machinery called a PA subunit, preventing it from functioning. Viruses that can’t replicate are not infectious, but this recent discovery shows that a protein named PB1-F2 prevents the human restriction factor, called HAX-1, from immobilizing the PA subunit within the avian influenza A virus. It appears to do so simply by binding to HAX-1 in a way that prevents the replication-stopping binding of HAX-1 to PA. “We started with a classical fishing expedition,” said Dr. Schmolke. “The goal was to identify human host proteins that interact with PB1-F2,” he said. “Within the top hits identified by mass spectrometry, we found HAX-1.” Further experiments by Dr. Schmolke’s group supports the hypothesis that the human protein, HAX-1, is likely a general defense against avian influenza viruses, but not against mammalian influenza viruses. “Avian viruses found a way to compensate for this restriction by expressing PB1-F2,” said Dr. Schmolke. Thus, it is one—of probably many—adaptations that enable it to cross the species barrier. Part of the motivation for the research was the knowledge, from phylogenetic studies, that PB1-F2, the HAX-1-blocking mechanism, is highly prevalent in avian influenza A viruses, but rare in swine and human viruses. Human viruses appear to have a HAX-1-resistant PA and thus do not require PB1-F2. A further step in this research will be to determine which sequences in PB1-F2 are required to disable HAX-1. “Then, the PB1-F2 sequences of different avian viruses could be sequenced to determine which are most likely to disable HAX-1, thus posing a threat to humans,” Dr. Schmolke added.