Pandemic influenza viruses--hoping for the road not taken.

ter analogous evolutionary divergence points, and they may not all take linear paths to inevitable outcomes. For instance, a novel avian influenza A (H7N9) virus has emerged in China.1 Because all known pandemic and other human, mammalian, and poultry influenza A viruses have descended from wild-bird viruses, it seems logical that any avian influenza A virus that becomes pandemic must have serially acquired signature mutations known to be associated with circulation in humans. It would follow that mutations distinguishing “avian-like” from “humanlike” viruses must be milestones on a fixed evolutionary pathway to potential pandemicity, including mutations affecting the hemagglutinin (HA) receptor–binding domain associated with efficient binding to human epithelial cells, polymerase mutations associated with efficient replication in human cells, and others. The fact that H7N9 isolates have some of these mutations1 has led to predictions of its evolution toward pandemicity. However, firm scientific evidence for such well-defined linear pathways is lacking. Since 1918, the emergence of four pandemic viruses has been documented, but scientists have found no evidence of a direct mutational mechanism2; conversely, many avian viruses have infected humans and rapidly developed such mutations without becoming pandemic. Rather than being indicators of inevitable pandemic progression, these mutations may simply be markers that any avian influenza virus is likely to develop when it replicates in human cells. In keeping with this interpretation, novel human H7N9 isolates have several “human-like” mutations affecting HA, viral polymerase, and other proteins, whereas temporally and geographically related avian H7N9 isolates do not.1 The critical but currently unanswerable question is whether every avian influenza virus capable of infecting humans can acquire serial pandemic-generating mutations without being limited by structural or functional evolutionary constraints — or whether pandemic viruses are rare entities whose complex gene constellations cannot easily be configured except by rare and still-obscure mechanisms. We do know that humans, who can be easily infected with avian influenza A viruses by experimental challenge, are naturally and repeatedly exposed to and often infected by many such avian viruses without generating pandemics — as evidenced by multiple epidemics and case clusters as well as by serosurveys.3,4 Given the potential daily exposures of millions of humans to various avian influenza viruses, Pandemic Influenza Viruses — Hoping for the Road Not Taken