Mutations in the NS1 C-terminal tail do not enhance replication or virulence of the 2009 pandemic H1N1 influenza A virus.
The 'classical' swine H1N1 influenza A virus lineage was established after the devastating 1918 human pandemic virus entered domestic pig herds. A descendent of this lineage recently re-emerged in humans as the 2009 pandemic H1N1 virus. Adaptation in pigs has led to several changes in the multifunctional viral NS1 protein as compared with the parental 1918 virus, most notably a K217E substitution that abolishes binding to host Crk/CrkL signalling adapters, and an 11 aa C-terminal truncation. Using reverse genetics, we reintroduced both these features into a prototype 2009 H1N1 strain, A/California/04/09. Restoration of Crk/CrkL binding or extension of NS1 to 230 aa had no impact on virus replication in human or swine cells. In addition, minimal effects on replication, pathogenicity and transmission were observed in mouse and ferret models. Our data suggest that the currently circulating 2009 H1N1 virus is optimized to replicate efficiently without requiring certain NS1 functions.
Department of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Benjamin G
BG
Hale
John
J
Steel
Balaji
B
Manicassamy
Rafael A
RA
Medina
Jianqiang
J
Ye
Danielle
D
Hickman
Anice C
AC
Lowen
Daniel R
DR
Perez
Adolfo
A
García-Sastre
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004196:Disease Outbreaks; D005289:Ferrets; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics* / Q000472:pathogenicity*; D007251:Influenza, Human / Q000453:epidemiology / Q000821:virology*; D051379:Mice; D008811:Mice, Inbred DBA; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk / Q000235:genetics / Q000378:metabolism; D013552:Swine; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D014774:Virulence; D014779:Virus Replication
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; C085820:INS1 protein, influenza virus; D009687:Nuclear Proteins; D050737:Proto-Oncogene Proteins c-crk; D017361:Viral Nonstructural Proteins