Informational: 2.1. Mutation from LPAI virus to HPAI virus

2.1. Mutation from LPAI virus to HPAI virus

A key event in the genesis of all HPAI viruses is conversion (mutation) of an H5 or H7 LPAI virus to an HPAI virus. This has occurred in the past following multiplication of LPAI viruses of these subtypes in chickens but it is not known whether this is an essential prerequisite.

Virulence of avian influenza viruses is a polygenic trait (Suarez et al, 2004) that usually results from insertion or substitution of multiple basic amino acids at the cleavage site of the HA protein. These are not normally present in LPAI viruses. This mutation allows the HA protein to be cleaved by a broad range of proteases, allowing the viruses to multiply systemically (Alexander, 2000). Other novel mechanisms for conversion of LPAI viruses to HPAI viruses have been described in outbreaks of HPAI in Chile (2002) and Canada (2004). These arose through recombination between the HA gene and that of another gene coding for an internal protein, leading to insertion of additional amino acids at the HA cleavage site (Suarez et al, 2004; Pasick et al, 2005). Modification of the cleavage site appears to be an essential condition, but is not the only factor that determines virulence (Londt et al, 2007).

Even though the molecular events surrounding mutation from an LPAI virus to an HPAI virus are known, the factors that lead to this mutation are not clear for many outbreaks of H5 and H7 avian influenza viruses, including the first of the Asian-lineage H5N1 HPAI viruses.

An HPAI virus has been generated experimentally by repeat passage of a LPAI virus through chickens by air sac and intracerebral inoculation (Ito et al, 2001) but the exact triggers for this change under natural conditions are not known. In some earlier outbreaks of HPAI, it was evident that the change from a LPAI virus to an HPAI virus followed introduction of LPAI virus to large flocks of commercial poultry. This change apparently occurred within a matter of days in some outbreaks (as was the case of the 2004 Canadian outbreak [Bowes et al, 2004]). On the other hand, in some Central American countries, low pathogenicity H5N2 strains have circulated in poultry for a number of years without developing into highly pathogenic strains. Even in Mexico, where mutation of a LPAI H5N2 virus to an HPAI virus occurred in 1994 and this HPAI virus strain was subsequently eliminated, H5N2 LPAI viruses continue to circulate (Villarreal, 2006) but have not reverted to high pathogenicity.

The Asian-lineage H5N1 HPAI viruses differ somewhat from those in earlier HPAI outbreaks in that the HPAI viruses first detected in 1996 were not eliminated, and have circulated in highly pathogenic form for over 11 years (Sims et al, 2005). These viruses have evolved considerably over this time, but no closely related low pathogenic precursor strains of the H5 subtype have been isolated, (Duan et al, 2007; Mukhtar et al, 2007). Presumably, such a virus existed prior to 1996 but has never been detected or reported (Sims et al, 2005). The HA and NA genes in LPAI viruses most closely related to those in Goose/Guangdong/1/96 were isolated experimentally from aquatic birds in Japan (Mukhtar et al, 2007).

All subsequent Asian-lineage H5N1 avian influenza viruses have remained highly pathogenic and their origins can be traced back to viruses similar to those found in geese in Guangdong in 1996 (Sims et al, 2005). Even those viruses that have infected domestic ducks subclinically in many parts of Asia retain the multiple basic amino acids at the cleavage site and are highly pathogenic for terrestrial poultry (Chen et al, 2004).

No evidence has been provided to indicate that the first Asian-lineage H5N1 HPAI virus emerged in an intensive poultry farm. If this conversion from LPAI to HPAI occurred in geese (the type of poultry from which it was first isolated), this would not have involved industrialized production facilities because geese in southern China were then reared mainly in small flocks with only a few large semi-intensive production units.

The lack of markers of adaptation to chickens (e.g. a deletion in the stalk of the NA glycoprotein (Matrosovich et al, 1999) in the original 1996 strains of H5N1 HPAI virus also suggests, but does not prove, that limited circulation of this virus occurred in chickens before 1997. A stalk deletion in the NA was not detected in viruses of this lineage until March 1997, when it was detected in a virus isolated from a dead chicken on a farm in the Hong Kong Special Administration Region (SAR) (Bender et al, 1999).

These observations, coupled with evidence that other HPAI viruses emerged in the early 20th century prior to intensification of the poultry industry, indicate that the circulation of a LPAI virus in industrialized poultry rearing systems, although considered an important factor in the emergence of some HPAI strains, is not an essential prerequisite for the genesis of an HPAI virus.

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