In vitro assessment of attachment pattern and replication efficiency of H5N1 influenza A viruses with altered receptor specificity.
The continuous circulation of the highly pathogenic avian influenza (HPAI) H5N1 virus has been a cause of great concern. The possibility of this virus acquiring specificity for the human influenza A virus receptor, alpha2,6-linked sialic acids (SA), and being able to transmit efficiently among humans is a constant threat to human health. Different studies have described amino acid substitutions in hemagglutinin (HA) of clinical HPAI H5N1 isolates or that were introduced experimentally that resulted in an increased, but not exclusive, binding of these virus strains to alpha2,6-linked SA. We introduced all previously described amino acid substitutions and combinations thereof into a single genetic background, influenza virus A/Indonesia/5/05 HA, and tested the receptor specificity of these 27 mutant viruses. The attachment pattern to ferret and human tissues of the upper and lower respiratory tract of viruses with alpha2,6-linked SA receptor preference was then determined and compared to the attachment pattern of a human influenza A virus (H3N2). At least three mutant viruses showed an attachment pattern to the human respiratory tract similar to that of the human H3N2 virus. Next, the replication efficiencies of these mutant viruses and the effects of three different neuraminidases on virus replication were determined. These data show that influenza virus A/Indonesia/5/05 potentially requires only a single amino acid substitution to acquire human receptor specificity, while at the same time remaining replication competent, thus suggesting that the pandemic threat posed by HPAI H5N1 is far from diminished.
Chutinimitkul
Salin
S
Department of Virology and National Influenza Center, Erasmus MC, P.O. Box 2040, 3000CA Rotterdam, Netherlands.
van Riel
Debby
D
Munster
Vincent J
VJ
van den Brand
Judith M A
JM
Rimmelzwaan
Guus F
GF
Kuiken
Thijs
T
Osterhaus
Albert D M E
AD
Fouchier
Ron A M
RA
de Wit
Emmie
E
D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D005289:Ferrets; D006389:Hemagglutinins, Viral / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000472:pathogenicity / Q000502:physiology; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D020125:Mutation, Missense; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000821:virology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D053585:Virus Attachment; D014779:Virus Replication
D006389:Hemagglutinins, Viral; D011991:Receptors, Virus; D014764:Viral Proteins; C458881:hemagglutinin fusogenic peptide, influenza virus; C487630:NA protein, influenza A virus; D009439:Neuraminidase
Science. 2007 Feb 2;315(5812):655-9
17272724
Virus Res. 2004 Jul;103(1-2):155-61
15163504
PLoS One. 2009 Nov 18;4(11):e7836
19924306
Virus Res. 1993 Aug;29(2):155-65
8212857
Virology. 1991 Jan;180(1):10-5
1984642
PLoS Pathog. 2008 Apr 11;4(4):e1000043
18404209
J Virol. 2000 Jul;74(13):6015-20
10846083
Nature. 2006 Nov 16;444(7117):378-82
17108965
Virology. 1994 Nov 15;205(1):17-23
7975212
N Engl J Med. 2009 Jun 18;360(25):2605-15
19423869
J Infect Dis. 2007 Jul 15;196(2):258-65
17570113
PLoS Pathog. 2009 Dec;5(12):e1000709
20041223
Am J Pathol. 2010 Apr;176(4):1614-8
20167867
Arch Virol. 2001;146(5):963-73
11448033
Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):286-91
19116267
J Gen Virol. 2008 Aug;89(Pt 8):1805-1810
18632950
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2800-5
18287068
Science. 2006 Apr 21;312(5772):399
16556800
J Virol. 2006 Aug;80(15):7469-80
16840327
Science. 2006 Apr 21;312(5772):404-10
16543414
PLoS Pathog. 2009 Jan;5(1):e1000252
19119420
Nat Biotechnol. 2008 Jan;26(1):107-13
18176555
Nature. 2006 Mar 23;440(7083):435-6
16554799
J Virol. 2007 Sep;81(18):9950-5
17626098
Vaccine. 2008 Sep 12;26 Suppl 4:D54-8
19230161
J Virol. 1993 Apr;67(4):1761-4
8445709
J Virol. 2000 Sep;74(18):8502-12
10954551
Rev Med Virol. 2002 May-Jun;12(3):159-66
11987141
Virology. 2000 Dec 20;278(2):587-96
11118381
Lancet. 2004 Apr 3;363(9415):1099-103
15064027
J Exp Med. 2006 Mar 20;203(3):689-97
16533883
Science. 2001 Sep 7;293(5536):1840-2
11546875
Science. 2009 Jul 24;325(5939):481-3
19574348
Virology. 2006 Jan 20;344(2):432-8
16226289
J Gen Virol. 2000 May;81(Pt 5):1283-91
10769071
J Virol. 1999 Aug;73(8):6743-51
10400772
Science. 2007 Aug 10;317(5839):825-8
17690300
Am J Pathol. 2007 Oct;171(4):1215-23
17717141
N Engl J Med. 2005 Jan 27;352(4):333-40
15668219