UniProt release 6.8

Major update of influenza A viruses: H5N1 pathogenicity

Influenza A viruses are named depending on their surface protein subtype, H for hemagglutinin and N for neuraminidase. There are 16 known H subtypes and 9 known N subtypes for influenza A virus, all of them infect birds, a few such as H1N1, H1N2 and H3N2 can infect human.

'Avian influenza' is used to name viruses commonly restricted to birds, such as H5,H7,H9,... subtypes. Most avian influenza subtypes cause very mild diseases, but the H5 and H7 subtypes can cause outbreaks involving massive deaths in domestic poultry. During these outbreaks, sporadic transmission to human has been reported. Fortunately humans are dead end hosts for these viruses, i.e. infected humans do not transmit the virus. Although few human cases of H7N7 and H9N2 have been documented, the major threat remains the H5N1 subtype.

H5N1 is not a new virus, it was isolated on birds in Scotland back in 1959 (hemagglutinin: P09345). It became famous after the first big outbreak in 1997 in Hong Kong, where 1.5 millions of poultry were affected and destroyed, and 18 human cases occurred, six of whom died (hemagglutinin: O56140). This was the first time an avian influenza A virus transmission directly from birds to humans had been found.

In 2003 two cases of H5N1 occurred in Hong Kong, one fatal. How or where these two family members were infected was not determined. In 2004 and 2005, severe outbreaks happened in Thailand, Vietnam, Cambodia and Indonesia, for a total of 130 human cases, 70 of whom died. Most of these cases occurred as a result of people having direct or close contact with infected poultry, however a few cases of human-to-human spread of H5N1 have occurred.

Why is H5N1 so deadly in poultry and humans? Presumably because of small sequence variations in hemagglutinin.

Hemaglutinin is present at the virion surface, and its function both to bind cellular receptor and induce fusion of viral and target cell membrane. In order to be able to promote fusion, the protein must be cleaved. In common influenza A viruses, the cleavage site is specific to proteases present in the respiratory tract. Hence influenza is restricted to infect this organ.

H5 and H7 have a completely different cleavage site, rich in arginine and lysine residues (RRRKKR in Hong Kong 1997: O56140), which can be processed by ubiquitous proteases: furins. This result in an infection of almost all host organs, and an acute pathology which can be quickly fatal.

Few antiviral drugs are effective against influenza. Zanamivir (Relenza) and oseltamivir (Tamiflu) are inhibitors of the neuraminidase (e.g. Q9W7Y7), amantadine and rimantadine are inhibitors of ion channel M2 protein (e.g. O70632). Unfortunately drug resistance evolves rapidly, and already a case of H5N1 resistant to Tamiflu has been reported (Nature 437:1108-1108(2005)).

The following are examples of updated influenza entries:

H5N1 isolated from human, in Hong Kong 1997:

Hemagglutinin: HEMA_IAHO3 (O56140) Neuraminidase: NRAM_IAHO3 (Q9W7Y7) M1: M1_IAHO3 (Q77Y95) M2: M2_IAHO3 (O70632) NS1 : NS1_IAHO3 (O56264) NEP: NEP_IAHO3 (O56263) PB1-F2 : PB1F2_IAHO3 (P0C0U0) Nucleoprotein: NCAP_IAHO3 (O92784) PA : PA_IAHO3 (O89752) PB1 : RDRP_IAHO3 (Q9WLS3) PB2: PB2_IAHO3 (O56266)

H5N1 isolated in 1959 on chicken:

Hemagglutinin: HEMA_IACKS (P09345)

Abbrev: EcoGene
Name  : Escherichia coli strain K12 genome database
LinkTp: Explicit
Server: http://www.ecogene.org/
Db_URL: www.ecogene.org/geneInfo.php?eg_id=%s
Cat   : Organism-specific gene databases