H5N1 influenza: a protean pandemic threat

Abstract

Infection with avian influenza A virus of the H5N1 subtype (isolates A/HK/212/03 and A/HK/213/03) was fatal to one of two members of a family in southern China in 2003. This incident was preceded by lethal outbreaks of H5N1 influenza in waterfowl, which are the natural hosts of these viruses and, therefore, normally have asymptomatic infection. The hemagglutinin genes of the A/HK/212/03-like viruses isolated from humans and waterfowl share the lineage of the H5N1 viruses that caused the first known cases of human disease in Hong Kong in 1997, but their internal protein genes originated elsewhere. The hemagglutinin of the recent human isolates has undergone significant antigenic drift. Like the 1997 human H5N1 isolates, the 2003 human H5N1 isolates induced the overproduction of proinflammatory cytokines by primary human macrophages in vitro, whereas the precursor H5N1 viruses and other H5N1 reassortants isolated in 2001 did not. The acquisition by the viruses of characteristics that enhance virulence in humans and waterfowl and their potential for wider distribution by infected migrating birds are causes for renewed pandemic concern.

Fig. 1.

Phylogenetic trees for the H5 HA1 (a), M (b), and NP (c) genes of influenza A viruses. The nucleotide sequences were analyzed with paup by using a maximum-parsimony algorithm. Nucleotides 70–1,033 of the HA1, 46–982 of the M, and 46–905 of the NP genes were analyzed. The HA1 tree is rooted to A/Japan/305+/57 (H2N2). The M and NP trees are rooted to A/Equine/Prague/1/56 (H7N7). The lengths of the horizontal lines are proportional to the minimum number of nucleotide differences required to join nodes. Names and abbreviations of viruses are as listed in Table 1 and ref. . Other sequences are available in GenBank. G1-like H9N2 and Y280-like H9N2 refer to the A/Quail/Hong Kong/G1/97-like and A/Duck/Hong Kong/Y280/97-like lineages of H9N2 viruses, respectively (27).

Fig. 2.

Expression of TNF-α and IP-10 protein in primary human macrophages infected in vitro with H5N1 viruses of the indicated genotypes. TNF-α and IP-10 were assayed in culture supernatants 6 h after inoculation with virus at a multiplicity of infection of 2.0.