Persistent host markers in pandemic and H5N1 influenza viruses

Abstract

Avian influenza viruses have adapted to human hosts, causing pandemics in humans. The key host-specific amino acid mutations required for an avian influenza virus to function in humans are unknown. Through multiple-sequence alignment and statistical testing of each aligned amino acid, we identified markers that discriminate human influenza viruses from avian influenza viruses. We applied strict thresholds to select only markers which are highly preserved in human influenza virus isolates over time. We found that a subset of these persistent host markers exist in all human pandemic influenza virus sequences from 1918, 1957, and 1968, while others are acquired as the virus becomes a seasonal influenza virus. We also show that human H5N1 influenza viruses are significantly more likely to contain the amino acid predominant in human strains for a few persistent host markers than avian H5N1 influenza viruses. This sporadic enrichment of amino acids present in human-hosted viruses may indicate that some H5N1 viruses have made modest adaptations to their new hosts in the recent past. The markers reported here should be useful in monitoring potential pandemic influenza viruses.

FIG. 1.

Host-differentiating sites are compared to those of pandemic strains. Each of the 32 host-differentiating sites is displayed and color coded by host. Avian is in blue, human in yellow. The intensity of color for each position is determined by the proportional Euclidean distance between hosts. Positions where the consensus residue of each pandemic strain agrees with the most frequent human amino acid are boxed. The 13 positions where all pandemic isolates surveyed absolutely agree with the most frequent human amino acid are indicated by arrows. Wherever the most frequently observed amino acid is neither the avian nor the human consensus residue, it appears in gray. Position numbers for the markers in each protein are given at the bottom (Pos).

FIG. 2.

Persistent host markers occur in known protein binding domains. The blue squares denote regions where the named protein is known to bind to a specific protein (see the text; data not shown) or the novel SH3 domain. The red lines denote host markers found in this study.

FIG. 3.

The preservation of host markers increases over time in human H1N1 viruses. The proportions of host markers acquired over time by H1N1 influenza viruses isolated from human hosts are plotted. All 32 markers are 99% persistent. The positions numbered in red are referred to in the text.