Pandemic threat posed by avian influenza A viruses

Abstract

Influenza pandemics, defined as global outbreaks of the disease due to viruses with new antigenic subtypes, have exacted high death tolls from human populations. The last two pandemics were caused by hybrid viruses, or reassortants, that harbored a combination of avian and human viral genes. Avian influenza viruses are therefore key contributors to the emergence of human influenza pandemics. In 1997, an H5N1 influenza virus was directly transmitted from birds in live poultry markets in Hong Kong to humans. Eighteen people were infected in this outbreak, six of whom died. This avian virus exhibited high virulence in both avian and mammalian species, causing systemic infection in both chickens and mice. Subsequently, another avian virus with the H9N2 subtype was directly transmitted from birds to humans in Hong Kong. Interestingly, the genes encoding the internal proteins of the H9N2 virus are genetically highly related to those of the H5N1 virus, suggesting a unique property of these gene products. The identification of avian viruses in humans underscores the potential of these and similar strains to produce devastating influenza outbreaks in major population centers. Although highly pathogenic avian influenza viruses had been identified before the 1997 outbreak in Hong Kong, their devastating effects had been confined to poultry. With the Hong Kong outbreak, it became clear that the virulence potential of these viruses extended to humans.

FIG. 1

“Habitat” of influenza A viruses. Ecological and phylogenetic studies suggest that wild waterfowl are the principal reservoirs for influenza A viruses, which occasionally are transmitted to other host animals such as horses, pigs, and chickens, leading to influenza outbreaks among these species. Some of the viruses may become established in these new hosts and cause epidemics and epizootics. Viruses are transmitted among these new host animals (e.g., between humans and pigs or between chickens and humans, as occurred in 1997 in Hong Kong).

FIG. 2

Structure of influenza A virus virions. Two glycoprotein spikes, HA and NA, and the M2 protein are embedded in the lipid bilayer derived from the host plasma membrane. The RNP consists of a viral RNA segment associated with the NP and the three polymerase proteins (PA, PB1, and PB2). The M1 protein is associated with both RNP and the viral envelope, while NS2 is associated with RNP through interaction with M1. NS1 is the only nonstructural protein of influenza A virus.

FIG. 3

Phylogenetic relationships among influenza A virus genes. These generalized phylogenetic trees are derived from references (NP, rooted to influenza virus NP), 80 (H1 HA, rooted to H2 HA), 164 (H2 HA, rooted to H5 HA), and 11 (H3 HA, rooted to H4 HA). Horizontal distances are proportional to the number of nucleotide differences needed to join the gene sequences, while vertical lines are used for spacing branches and labels. The arrow at the left of each tree represents the node connecting the influenza B virus homologue. Equine 1, H7N7 subtype (e.g., A/Equine/Prague/56); Equine 2, H3N8 subtype (e.g., A/Equine/Miami/63); Human NP, H1N1, H2N2 and H3N2 subtypes; Swine, classic swine viruses of the H1N1 subtype (e.g., A/Swine/Iowa/15/30); Gull, H13 gull viruses; Avian-Swine, European swine viruses derived from an avian virus.

FIG. 4

Possible origins of pandemic influenza viruses. Phylogenetic studies suggest that an avian influenza virus was transmitted to humans, leading to the 1918 pandemic. A reassortant virus possessing its PB1, HA, and NA genes from a Eurasian avian virus, with the remainder coming from an H1N1 human virus, caused the Asian pandemic of 1957. The H1N1 virus subsequently disappeared from humans. In 1968, a reassortant possessing its PB1 and HA genes from a Eurasian avian virus and the remainder from an H2N2 human virus emerged, followed by the disappearance of the H2N2 virus. In 1977, a virus genetically almost identical to those circulating in humans in 1950 appeared and spread among children and young adults. The H1N1 and H3N2 viruses are now cocirculating in humans.

FIG. 5

Models for the generation of pandemic influenza virus strains in pigs. In the classical genetic reassortment model (A), avian and human viruses bind respectively to NeuAcα2,3Gal and NeuAcα2,6Gal (α2,3 and α2,6) linkages in the pig trachea, setting the stage for the emergence of a reassortant that infects a large fraction of the human population. The segments in the center of each particle represent the viral genome. The reassortant HA gene (black) is derived from an avian virus. In the adaptation model (B), avian viruses acquire the ability to replicate efficiently in humans during adaptation to the NeuAcα2,6Gal linkage in pigs. This change is mediated by a mutation in the HA gene. Alternatively, an avian influenza virus is transmitted directly to humans, where it reassorts with a human virus (C) or acquires the ability to recognize the NeuAcα2,6Gal linkage after direct introduction from birds (D), leading to efficient replication in humans. Reprinted from reference with permission of the American Society for Microbiology.