title: Genetic requirement for hemagglutinin glycosylation and its implications for influenza A H1N1 virus evolution.
abstract: Influenza A virus has evolved and thrived in human populations. Since the 1918 influenza A pandemic, human H1N1 viruses had acquired additional N-linked glycosylation (NLG) sites within the globular head region of hemagglutinin (HA) until the NLG-free HA head pattern of the 1918 H1N1 virus was renewed with the swine-derived 2009 pandemic H1N1 virus. Moreover, the HA of the 2009 H1N1 virus appeared to be antigenically related to that of the 1918 H1N1 virus. Hence, it is possible that descendants of the 2009 H1N1 virus might recapitulate the acquisition of HA head glycosylation sites through their evolutionary drift as a means to evade preexisting immunity. We evaluate here the evolution signature of glycosylations found in the globular head region of H1 HA in order to determine their impact in the virulence and transmission of H1N1 viruses. We identified a polymorphism at HA residue 147 associated with the acquisition of glycosylation at residues 144 and 172. By in vitro and in vivo analyses using mutant viruses, we also found that the polymorphism at HA residue 147 compensated for the loss of replication, virulence, and transmissibility associated with the presence of the N-linked glycans. Our findings suggest that the polymorphism in H1 HA at position 147 modulates viral fitness by buffering the constraints caused by N-linked glycans and provide insights into the evolution dynamics of influenza viruses with implications in vaccine immunogenicity.
authors: Department of Microbiology, College of Medicine, Hallym University, Chuncheon, Gangwon-do, Korea.
authors: Jin Il
authors: JI
authors: Kim
authors: Ilseob
authors: I
authors: Lee
authors: Sehee
authors: S
authors: Park
authors: Min-Woong
authors: MW
authors: Hwang
authors: Joon-Yong
authors: JY
authors: Bae
authors: Sangmoo
authors: S
authors: Lee
authors: Jun
authors: J
authors: Heo
authors: Mee Sook
authors: MS
authors: Park
authors: Adolfo
authors: A
authors: García-Sastre
authors: Man-Seong
authors: MS
authors: Park
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D001835:Body Weight; D004285:Dogs; D019143:Evolution, Molecular; D006031:Glycosylation; D006168:Guinea Pigs; D057809:HEK293 Cells; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics* / Q000472:pathogenicity*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D009976:Orthomyxoviridae Infections / Q000635:transmission / Q000821:virology*; D011110:Polymorphism, Genetic / Q000235:genetics; D011487:Protein Conformation; D056910:Republic of Korea; D017422:Sequence Analysis, DNA; D014774:Virulence
chemical_list: C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus
references: Nature. 2009 Jun 25;459(7250):1122-5
references: 19516283
references: Proc Natl Acad Sci U S A. 1987 Jan;84(1):36-40
references: 3467357
references: Yonsei Med J. 2012 Sep;53(5):886-93
references: 22869469
references: Science. 2010 Apr 16;328(5976):357-60
references: 20339031
references: PLoS Pathog. 2010 Nov 24;6(11):e1001211
references: 21124818
references: J Exp Med. 1978 Aug 1;148(2):383-92
references: 359746
references: Annu Rev Biochem. 2000;69:531-69
references: 10966468
references: Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):E1417-22
references: 22106257
references: Bull World Health Organ. 1985;63(2):273-7
references: 2410157
references: MMWR Morb Mortal Wkly Rep. 2009 May 22;58(19):521-4
references: 19478718
references: J Exp Med. 1936 Apr 30;63(5):669-84
references: 19870496
references: PLoS One. 2012;7(2):e32119
references: 22355413
references: Arch Virol. 2004 Aug;149(8):1663-71
references: 15290389
references: Nature. 2009 Aug 20;460(7258):1021-5
references: 19672242
references: JAMA. 1977 Mar 21;237(12):1225-8
references: 576459
references: Science. 2010 Mar 26;327(5973):1563-4
references: 20339037
references: J Phys Chem A. 2008 Oct 30;112(43):10939-48
references: 18839935
references: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9988-92
references: 16785447
references: N Engl J Med. 2009 Nov 12;361(20):1945-52
references: 19745214
references: Science. 2004 Mar 19;303(5665):1866-70
references: 14764887
references: J Virol. 2012 Jan;86(2):982-90
references: 22072785
references: Wkly Epidemiol Rec. 1997 Feb 28;72(9):57-61
references: 9057482
references: J Virol. 2006 Aug;80(16):8060-8
references: 16873262
references: Nat Biotechnol. 2009 Jun;27(6):510-3
references: 19513050
references: PLoS Pathog. 2010 Jan 29;6(1):e1000745
references: 20126449
references: Influenza Other Respir Viruses. 2011 May;5(3):157-66
references: 21477134
references: J Virol. 2000 Jul;74(14):6316-23
references: 10864641
references: Vaccine. 2012 Jun 22;30(30):4419-34
references: 22537992
references: J Virol. 1997 Nov;71(11):8377-84
references: 9343193
references: Virology. 2011 Apr 25;413(1):139-47
references: 21397290
references: Science. 2009 Jul 10;325(5937):197-201
references: 19465683
references: Science. 2009 Oct 30;326(5953):734-6
references: 19900932
references: Science. 2004 Mar 19;303(5665):1838-42
references: 14764886
references: MMWR Morb Mortal Wkly Rep. 1986 Aug 15;35(32):517-21
references: 3090424
references: Proc Natl Acad Sci U S A. 1984 Mar;81(6):1779-83
references: 6584912
references: Vet Microbiol. 2000 May 22;74(1-2):71-5
references: 10799779
references: Wkly Epidemiol Rec. 1998 Feb 27;73(9):56-61
references: 9523511
references: J Virol. 1993 Jun;67(6):3048-60
references: 8497042
references: BMB Rep. 2012 Nov;45(11):653-8
references: 23187005
references: Expert Rev Mol Med. 2010 Dec 09;12:e39
references: 21144091
references: Wkly Epidemiol Rec. 1996 Nov 22;71(47):353-7
references: 8973138
references: Sci Transl Med. 2010 Mar 24;2(24):24ra21
references: 20375007
references: Nat Med. 2004 Dec;10(12 Suppl):S82-7
references: 15577936
references: PLoS One. 2011;6(7):e22844
references: 21829533
references: J Gen Virol. 2002 May;83(Pt 5):1137-1146
references: 11961269
references: J Virol. 1999 Nov;73(11):9679-82
references: 10516084
references: J Infect Dis. 1997 Aug;176 Suppl 1:S24-8
references: 9240690