The Effect of the PB2 Mutation 627K on Highly Pathogenic H5N1 Avian Influenza Virus Is Dependent on the Virus Lineage

Abstract

The 50-92 PB2 627K was genetically unstable during virus propagation, resulting in reversion to PB2 627E or the accumulation of the additional mutation PB2 628R and/or a synonymous mutation from an A to a G nucleotide at nucleotide position 1869 (PB2 A1869G). Intriguingly, PB2 628R and/or A1869G appeared to improve the genetic stability of 50-92 PB2 627K. However, the replication of 50-92 PB2 627K in conjunction with these stabilizing mutations was significantly restricted in experimentally infected chickens, where reversion to PB2 627E occurred. In contrast, no significant effects on viral fitness were observed for Ty/05 PB2 627E or 627K in in vitro or in vivo experiments. Our observations suggest that PB2 627K is supported in Eurasianlineage viruses; in contrast, PB2 627K carries a significant fitness cost in the historical pre-Asian 50-92 virus.

How host genetics dictates successful viral zoonosis

“…Mutations in viral PB2 PB2-E627K, others observed as well [63][64][65] SIVcpz APOBEC3H restriction factor…”

“…This is, in fact, the basis of successful treatment of HIV infections with multidrug cocktails; while HIV can easily mutate to escape one drug, no single viral genome acquires the multiple drug escape mutations required for viral replication in a multiple-drug-treated host. Alarmingly, some of the H5N1 influenza viruses that are currently circulating in the avian reservoir already harbor PB2 mutations that would make them compatible with the human ANP32A [64,73]. Likewise, it is known that bat coronaviruses require mutations in their surface glycoprotein (spike) in order to use the human ortholog of their receptor, ACE2 ( Table 2).…”

Viral factors in influenza pandemic risk assessment

“…Such evolution has been observed in a fatal human case of influenza A/H7N7 (Jonges et al, 2014) and in mouse experiments following serial lung passage using an isolate from this outbreak (de Jong et al, 2013). Lys at position 627 has also been associated with greater severity in zoonotic H7N9 (Sha et al, 2016) and H5N1 (de Jong et al, 2006) cases However, reverse genetics experiments show that certain strains of avian influenza may be less able to accept these mutations than others (Long et al, 2013). …”

“…Many H5N1 viruses that circulate today in the avian reservoir already have mutations in PB2 at 627 (Long et al, 2013) or 701 (de Jong et al, 2006), likely resulting from the reintroduction of mammalian-adapted strains back into the wild bird reservoir. These have been associated in human infections with more severe cases (de Jong et al, 2006).…”

Ethical Alternatives to Experiments with Novel Potential Pandemic Pathogens

“…Elevated virulence, transmissibility (H5N1, H1N1, H7N7, etc.) [63][64][65][66] Unaffected virulence or transmissibility (H1N1pdm) [67]; decreased fitness (older H5N1) [66] NA H275Y Oseltamivir resistance, fitness crippled (H1N1) [68,69] Oseltamivir resistance, fitness increased in absence of drug (H1N1) [68,70] HA LS, 158,224,226 Mammalian transmission (H5N1 from Indonesia and Viet Nam) [1,2] No switch to mammalian sialic acid binding (H5N1 from Egypt) [50] Polybasic HA cleavage site High avian pathogenicity (many H5 and H7 viruses) [71,72] Low avian pathogenicity (four H5 isolates) [73] HA, hemagglutinin; NA, neuraminidase. doi:10.1371/journal.pmed.1001646.t001 Table 2.…”