No. 8: Avian Influenza Virus (H5N1)—A Few Amino-Acid Substitutions Shy of a Pandemic
As of December 18, the World Health Organization reported 77 cases of avian influenza worldwide, most of which occurred in
The reason we continue to care about avian influenza, beyond its documented and would-be effects on the commercial poultry industry (among other things), is the enduring potential of the virus to mutate, thereby enabling person-to-person transmission and blowing the human race to kingdom come. Veterinary investigators in
Hatta et al assessed the growth and replication of 2 highly virulent H5N1 isolates, VN1203 and VN1204, which were cultivated from the same 10-year-old Vietnamese boy who died of avian influenza in 2004 (Maines TR et al. J Virol. 2005; 79:11788–11800.). The 2 isolates differ in their coding for a total of 6 amino acids, but the authors elected to concentrate on the difference at position 627 of the cap-binding transcriptase (PB2) protein, because the host specificity of influenza A viruses (that is, human vs avian) appears to be determined, at least in part, at this site.† VN1203 codes for lysine (Lys) at the 627 position, and VN1204 codes of glutamate (Glu). As a rough generalization, most human subtypes have
The authors observed that Lys-encoded VN1203 and an engineered mutant of VN1204 with
It is therefore proposed that several H5N1 mutations, including the PB2 mutation, are necessary to confer efficient person-to-person transmission of avian influenza. Another cited mutation of importance consists of amino-acid substitutions in the viral-surface glycoprotein hemmaglutinin (HA), which detemines host-cell recognition. Mutated variants of HA bind to saccharide-containing cell receptors with either a terminating sialic acid α-2,3-galactose (SAα2,3Gal) on avian cells or sialic acid α-2,6-galactose (SAα2,6Gal) on human cells. The authors speculate that PB2-627Lys (which broadens susceptible cell types and enables low-temperature replication), SAα2,6Gal recognition (which enables human-cell binding), and other as-yet-unknown mutations are necessary for a human pandemic.
* I’m not sure why WHO makes a point of identifying these commercial birds as “free-range,” unless they were exceptionally free ranging.
† In addition, the PB2-627Lys variant may be associated with higher virulence and heartier replication capabilities. Specifically, the activity of its RNA polymerase is efficient at relatively low temperatures.
‡ A curious aside is that, in mice, titers of the engineered VN1204PB2-627Lys were appreciably higher than those of VN1203 (which also has PB2–627Lys), suggesting that coding differences beyond the 627 position determine growth efficiency of the virus.