Abstract
Avian influenza viruses (AIVs) periodically cross species barriers and infect humans. The likelihood that an AIV will evolve mammalian transmissibility depends on acquiring and selecting mutations during spillover, but data from natural infection is limited. We analyze deep sequencing data from infected humans and domestic ducks in Cambodia to examine how H5N1 viruses evolve during spillover. Overall, viral populations in both species are predominated by low-frequency (<10%) variation shaped by purifying selection and genetic drift, and half of the variants detected within-host are never detected on the H5N1 virus phylogeny. However, we do detect a subset of mutations linked to human receptor binding and replication (PB2 E627K, HA A150V, and HA Q238L) that arose in multiple, independent humans. PB2 E627K and HA A150V were also enriched along phylogenetic branches leading to human infections, suggesting that they are likely human-adaptive. Our data show that H5N1 viruses generate putative human-adapting mutations during natural spillover infection, many of which are detected at >5% frequency within-host. However, short infection times, genetic drift, and purifying selection likely restrict their ability to evolve extensively during a single infection. Applying evolutionary methods to sequence data, we reveal a detailed view of H5N1 virus adaptive potential, and develop a foundation for studying host-adaptation in other zoonotic viruses.
Highlights
Influenza virus cross-species transmission poses a continual threat to human health
H5N1 viruses currently cannot replicate and transmit efficiently among humans, but animal infection studies and modeling experiments have suggested that human adaptation may require only a few mutations
We analyze a unique dataset of deep sequence data from H5N1 virus-infected humans and domestic ducks in Cambodia
Summary
Influenza virus cross-species transmission poses a continual threat to human health. H5N1 viruses are endemic in domestic birds in some countries[2,3,4], and concern remains that continued human infection may one day facilitate human adaptation. Subsequent modeling studies suggest that within-host dynamics are conducive to generating human-transmissible viruses, but that these viruses may remain at frequencies too low for transmission[14,15]. These studies offer critical insight for H5N1 virus risk assessment, it is unclear whether they adequately describe how cross-species transmission proceeds in nature
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
