Before 1997, no evidence had indicated that H5 influenza viruses could infect humans and cause fatal disease. The H7 influenza viruses were known to cause conjunctivitis in humans, and serologic studies provided evidence of subclinical human infection with the subtypes prevalent in avian live poultry markets (4
). The precursor of the H5N1 influenza virus that spread to humans in 1997 was first detected in Guangdong, China, in 1996, when it caused a moderate number of deaths in geese and attracted very little attention (5
). This goose virus acquired internal gene segments from influenza viruses later found in quail (A/Quail/HK/G1/97 [H9N2]) and also acquired the neuraminidase gene segment from a duck virus (A/Teal/HK/W312/97 [H6N1]) before the goose virus became widespread in live poultry markets in Hong Kong and killed 6 of 18 infected persons (6,7
). This H5N1 virus was eradicated by culling all domestic poultry in Hong Kong, and the genotype has not been detected since that time. However, different reassortants continued to emerge from goose and duck reservoirs (8
) that contained the same H5 HA glycoprotein but had various internal genes. The H5N1 viruses continued to evolve, and in late 2002, a single genotype was responsible for killing most wild, domestic, and exotic waterfowl in Hong Kong nature parks (9,10
). This genotype of H5N1 spread to humans in Hong Kong in February 2002, killing 1 of 2 infected persons (11
), and was the precursor of the Z genotype that became dominant. The Z genotype spread in an unprecedented fashion across Southeast Asia, affecting Vietnam, Thailand, Indonesia, Cambodia, Laos, Korea, Japan, China, and later Malaysia. Further analysis showed that the H5N1 influenza viruses that caused outbreaks in poultry in Japan and Korea were genetically different from those in the other countries (the V genotype) (12,13
). The phylogeny of the recent Z genotype viruses showed that viruses isolated in Vietnam and Thailand formed a cluster that remained distinct from those isolated in Indonesia.
To date, >140 million domesticated birds have been killed by the virus or culled to stem its spread; as of December 2005, >130 persons have been infected in Vietnam, Thailand, Indonesia, Cambodia, and China, and 70 have died (42 in Vietnam, 14 in Thailand, 8 in Indonesia, 4 in Cambodia, and 2 in China). These recent H5N1 influenza viruses have acquired the unprecedented and disturbing capability to infect humans; to cause neurotropic disease and a high proportion of deaths in waterfowl in nature; to cause death in and be transmitted among felid species, including domestic cats (14
); and to cause neurotropic disease and death in ferrets and mice (15
). These incremental changes intensify concern about this H5N1 virus' pandemic potential. These traits are likely to have been acquired initially by reassortment in 2001 and 2002, when a plethora of different genotypes were detected in poultry markets and later in farms in Hong Kong (13
). These genes were presumably acquired from viruses found in waterfowl in Southeast Asia, but the actual gene donors have not yet been identified. Since late 2002, the Z genotype has become dominant, but phylogenetically distinguishable viruses have continued to cocirculate in Indonesia and western China. These characteristics have been acquired mainly through mutations in the RNA polymerase (PB2) gene, insertions in the HA gene, and deletions in the NA and nonstructural (NS) genes. Thus, the H5N1 viruses continue to evolve, initially by reassortment and more recently by mutation and deletion (16,17
). While most H5N1 influenza viruses isolated from avian species in Asia since 1997 are highly pathogenic in gallinaceous poultry, they show heterogeneous pathogenicity in other species.
In domestic ducks, the pathogenicity of the H5N1 viruses varies from high to nonpathogenic. In ferrets, most avian isolates replicate and cause respiratory tract infection, while a few strains are highly pathogenic and neurotropic (causing hind leg paralysis), and the virus has been isolated from the brain (15
). In contrast, all isolates from humans are highly pathogenic to ferrets. A similar pattern is found in experimental infection of mice, in which most avian isolates cause respiratory infection.