Hemagglutinin (influenza)#Subtypes

Hemagglutinin (HA) in influenza A virus (IAV) has at least 18 different subtypes.{{Cite web |last=CDC |date=2023-03-30 |title=Types of Influenza Viruses |url=https://www.cdc.gov/flu/about/viruses/types.htm |access-date=2024-05-12 |website=Centers for Disease Control and Prevention |language=en-us}} These subtypes are named H1 through H18. H16 was discovered in 2004 on IAVs isolated from black-headed gulls from Sweden and Norway. H17 was discovered in 2012 in fruit bats.{{cite journal | vauthors = Fouchier RA, Munster V, Wallensten A, Bestebroer TM, Herfst S, Smith D, Rimmelzwaan GF, Olsen B, Osterhaus AD | title = Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls | journal = Journal of Virology | volume = 79 | issue = 5 | pages = 2814–22 | date = March 2005 | pmid = 15709000 | pmc = 548452 | doi = 10.1128/JVI.79.5.2814-2822.2005 }}{{cite web | title = Unique new flu virus found in bats | url = http://www.nhs.uk/news/2012/03march/Pages/cdc-finds-h17-bat-influenza.aspx | archive-url = https://web.archive.org/web/20120520065657/http://www.nhs.uk/news/2012/03march/Pages/cdc-finds-h17-bat-influenza.aspx | archive-date=20 May 2012 }} Most recently, H18 was discovered in a Peruvian bat in 2013.{{cite journal | vauthors = Tong S, Zhu X, Li Y, Shi M, Zhang J, Bourgeois M, Yang H, Chen X, Recuenco S, Gomez J, Chen LM, Johnson A, Tao Y, Dreyfus C, Yu W, McBride R, Carney PJ, Gilbert AT, Chang J, Guo Z, Davis CT, Paulson JC, Stevens J, Rupprecht CE, Holmes EC, Wilson IA, Donis RO | title = New world bats harbor diverse influenza A viruses | journal = PLOS Pathogens | volume = 9 | issue = 10 | pages = e1003657 | date = October 2013 | pmid = 24130481 | pmc = 3794996 | doi = 10.1371/journal.ppat.1003657 | doi-access = free }} The first three hemagglutinins, H1, H2, and H3, are found in influenza viruses that infect humans. By phylogenetic similarity, the HA proteins are divided into 2 groups, with H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, and H18 belonging to group 1 and the rest in group 2.{{cite journal | vauthors = Sutton TC, Chakraborty S, Mallajosyula VV, Lamirande EW, Ganti K, Bock KW, Moore IN, Varadarajan R, Subbarao K | title = Protective efficacy of influenza group 2 hemagglutinin stem-fragment immunogen vaccines | journal = npj Vaccines | volume = 2 | issue = 1 | pages = 35 | date = 15 December 2017 | pmid = 29263889 | pmc = 5732283 | doi = 10.1038/s41541-017-0036-2 }} The serotype of IAV is determined by the HA and neuraminidase (NA) proteins expressed on its surface.{{Cite web|url=https://www.cdc.gov/flu/avianflu/influenza-a-virus-subtypes.htm|title=Influenza Type A Viruses|work= Avian Influenza (Flu)|date=2017-04-19|publisher=CDC|access-date=2018-08-27}} Neuraminidase has 11 known subtypes; hence, influenza viruses are named according to the combinations of HA and NA proteins expressed (e.g., H1N1 and H5N2).

File:Flu und legende color c.jpg

A highly pathogenic avian influenza A virus, A(H5N1), is known to infect humans as well as its original avian hosts, albeit quite infrequently. It has been reported that single amino acid changes in the virus's H5 hemagglutinin have been found in human patients that "can significantly alter receptor specificity of avian H5N1 viruses, providing them with an ability to bind to receptors optimal for human influenza viruses."{{cite journal | vauthors = Suzuki Y | title = Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses | journal = Biological & Pharmaceutical Bulletin | volume = 28 | issue = 3 | pages = 399–408 | date = March 2005 | pmid = 15744059 | doi = 10.1248/bpb.28.399 | doi-access = free }}{{cite journal | vauthors = Gambaryan A, Tuzikov A, Pazynina G, Bovin N, Balish A, Klimov A | title = Evolution of the receptor binding phenotype of influenza A (H5) viruses | journal = Virology | volume = 344 | issue = 2 | pages = 432–8 | date = January 2006 | pmid = 16226289 | doi = 10.1016/j.virol.2005.08.035 | doi-access = free }} This finding seems to explain how an H5N1 virus that normally does not infect humans can mutate and become able to efficiently infect human cells. The hemagglutinin of the H5N1 virus has been associated with its high degree of pathogenicity, apparently due to its ease of conversion to an active form by proteolysis.{{cite journal | vauthors = Hatta M, Gao P, Halfmann P, Kawaoka Y | title = Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses | journal = Science | volume = 293 | issue = 5536 | pages = 1840–2 | date = September 2001 | pmid = 11546875 | doi = 10.1126/science.1062882 | bibcode = 2001Sci...293.1840H | s2cid = 37415902 }}{{cite journal | vauthors = Senne DA, Panigrahy B, Kawaoka Y, Pearson JE, Süss J, Lipkind M, Kida H, Webster RG | title = Survey of the hemagglutinin (HA) cleavage site sequence of H5 and H7 avian influenza viruses: amino acid sequence at the HA cleavage site as a marker of pathogenicity potential | journal = Avian Diseases | volume = 40 | issue = 2 | pages = 425–37 | year = 1996 | pmid = 8790895 | doi = 10.2307/1592241 | jstor = 1592241 }}

HA is a homotrimeric integral membrane glycoprotein. It has C3 molecular symmetry. It is shaped like a cylinder, and is approximately 13.5 nanometres long.{{cite journal | vauthors = Wilson IA, Skehel JJ, Wiley DC | title = Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution | journal = Nature | volume = 289 | issue = 5796 | pages = 366–73 | date = January 1981 | pmid = 7464906 | doi = 10.1038/289366a0 | bibcode = 1981Natur.289..366W | s2cid = 4327688 }}{{cite journal | vauthors = Boonstra S, Blijleven JS, Roos WH, Onck PR, van der Giessen E, van Oijen AM | title = Hemagglutinin-Mediated Membrane Fusion: A Biophysical Perspective | journal = Annual Review of Biophysics | volume = 47 | issue = 1 | pages = 153–173 | date = May 2018 | pmid = 29494252 | doi = 10.1146/annurev-biophys-070317-033018 | url = https://pure.rug.nl/ws/files/55109243/Hemagglutinin_Mediated_Membrane_Fusion.pdf }} HA trimer is made of three identical monomers. Each monomer is made of an intact HA0 single polypeptide chain with HA1 and HA2 regions that are linked by 2 disulfide bridges.{{cite journal | vauthors = Di Lella S, Herrmann A, Mair CM | title = Modulation of the pH Stability of Influenza Virus Hemagglutinin: A Host Cell Adaptation Strategy | journal = Biophysical Journal | volume = 110 | issue = 11 | pages = 2293–2301 | date = June 2016 | pmid = 27276248 | pmc = 4906160 | doi = 10.1016/j.bpj.2016.04.035 | bibcode = 2016BpJ...110.2293D }} Each HA2 region adopts alpha helical coiled coil structure and sits on top of the HA1 region, which is a small globular domain that consists of a mix of α/β structures.{{cite book | vauthors = Smrt ST, Lorieau JL |volume=966 |date=2016 |series=Advances in Experimental Medicine and Biology|pages=37–54|publisher=Springer Singapore|doi=10.1007/5584_2016_174|pmid=27966108 |isbn=9789811069215 |title=Protein Reviews |chapter=Membrane Fusion and Infection of the Influenza Hemagglutinin }} The HA trimer is synthesized as inactive precursor protein HA0 to prevent any premature and unwanted fusion activity and must be cleaved by host proteases in order to be infectious. At neutral pH, the 23 residues near the N-terminus of HA2, also known as the fusion peptide that is eventually responsible for fusion between viral and host membrane, is hidden in a hydrophobic pocket between the HA2 trimeric interface.{{cite journal | vauthors = Wiley DC, Skehel JJ | title = The structure and function of the hemagglutinin membrane glycoprotein of influenza virus | journal = Annual Review of Biochemistry | volume = 56 | issue = 1 | pages = 365–94 | date = June 1987 | pmid = 3304138 | doi = 10.1146/annurev.bi.56.070187.002053 }} The C-terminus of HA2, also known as the transmembrane domain, spans the viral membrane and anchors protein to the membrane.{{Cite book | vauthors = Strauss JH, Strauss EG |title=Viruses and human disease |date=2008|publisher=Elsevier / Academic Press |isbn=9780080553160|edition= 2nd|location=Amsterdam|oclc=630107686}}

;HA1

: HA1 is mostly composed of antiparallel beta-sheets.

;HA2

:HA2 domain contains three long alpha helices, one from each monomer. Each of these helices is connected by a flexible, loop region called Loop-B (residue 59 to 76).{{cite journal | vauthors = Stevens J, Corper AL, Basler CF, Taubenberger JK, Palese P, Wilson IA | title = Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus | journal = Science | volume = 303 | issue = 5665 | pages = 1866–70 | date = March 2004 | pmid = 14764887 | doi = 10.1126/science.1093373 | bibcode = 2004Sci...303.1866S | s2cid = 42010652 | doi-access = free }}

HA plays two key functions in viral entry. Firstly, it allows the recognition of target vertebrate cells, accomplished through the binding to these cells' sialic acid-containing receptors. Secondly, once bound it facilitates the entry of the viral genome into the target cells by causing the fusion of host endosomal membrane with the viral membrane.{{cite book |vauthors=White JM, Hoffman LR, Arevalo JH, etal |chapter=Attachment and entry of influenza virus into host cells. Pivotal roles of hemagglutinin |veditors=Chiu W, Burnett RM, Garcea RL |title=Structural Biology of Viruses |url=https://archive.org/details/structuralbiolog0000unse_y3b6 |url-access=registration |publisher=Oxford University Press |year=1997 |pages=[https://archive.org/details/structuralbiolog0000unse_y3b6/page/80 80]–104 }}

Specifically, the HA1 domain of the protein binds to the monosaccharide sialic acid which is present on the surface of its target cells, allowing attachment of viral particle to the host cell surface. HA17 and HA18 have been described to bind MHC class II molecules as a receptor for entry rather than sialic acid.{{cite journal | vauthors = Karakus U, Thamamongood T, Ciminski K, Ran W, Günther SC, Pohl MO, Eletto D, Jeney C, Hoffmann D, Reiche S, Schinköthe J, Ulrich R, Wiener J, Hayes MG, Chang MW, Hunziker A, Yángüez E, Aydillo T, Krammer F, Oderbolz J, Meier M, Oxenius A, Halenius A, Zimmer G, Benner C, Hale BG, García-Sastre A, Beer M, Schwemmle M, Stertz S | title = MHC class II proteins mediate cross-species entry of bat influenza viruses | journal = Nature | volume = 567 | issue = 7746 | pages = 109–112 | date = March 2019 | pmid = 30787439 | doi = 10.1038/s41586-019-0955-3 | s2cid = 67769877 | bibcode = 2019Natur.567..109K }} The host cell membrane then engulfs the virus, a process known as endocytosis, and pinches off to form a new membrane-bound compartment within the cell called an endosome. The cell then attempts to begin digesting the contents of the endosome by acidifying its interior and transforming it into a lysosome. Once the pH within the endosome drops to about 5.0 to 6.0, a series of conformational rearrangement occurs to the protein. First, fusion peptide is released from the hydrophobic pocket and HA1 is dissociated from HA2 domain. HA2 domain then undergoes extensive conformation change that eventually bring the two membranes into close contact.{{citation needed|date=August 2022}}

This so-called "fusion peptide" that was released as pH is lowered, acts like a molecular grappling hook by inserting itself into the endosomal membrane and locking on. Then, HA2 refolds into a new structure (which is more stable at the lower pH), it "retracts the grappling hook" and pulls the endosomal membrane right up next to the virus particle's own membrane, causing the two to fuse together. Once this has happened, the contents of the virus such as viral RNA are released in the host cell's cytoplasm and then transported to the host cell nucleus for replication.{{cite journal | vauthors = Mair CM, Ludwig K, Herrmann A, Sieben C | title = Receptor binding and pH stability – how influenza A virus hemagglutinin affects host-specific virus infection | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1838 | issue = 4 | pages = 1153–1168 | date = April 2014 | pmid = 24161712 | doi = 10.1016/j.bbamem.2013.10.004 | doi-access = free }}

Since hemagglutinin is the major surface protein of the influenza A virus and is essential to the entry process, it is the primary target of neutralizing antibodies. {{citation needed|date=August 2022}}These antibodies against flu have been found to act by two different mechanisms, mirroring the dual functions of hemagglutinin:

Some antibodies against hemagglutinin act by inhibiting attachment. This is because these antibodies bind near the top of the hemagglutinin "head" (blue region in figure above) and physically block the interaction with sialic acid receptors on target cells.{{cite journal | vauthors = Goh BC, Rynkiewicz MJ, Cafarella TR, White MR, Hartshorn KL, Allen K, Crouch EC, Calin O, Seeberger PH, Schulten K, Seaton BA | title = Molecular mechanisms of inhibition of influenza by surfactant protein D revealed by large-scale molecular dynamics simulation | journal = Biochemistry | volume = 52 | issue = 47 | pages = 8527–38 | date = November 2013 | pmid = 24224757 | pmc = 3927399 | doi = 10.1021/bi4010683 }}

This group of antibodies acts by preventing membrane fusion (only in vitro; the efficacy of these antibodies in vivo is believed to be a result of antibody-dependent cell-mediated cytotoxicity and the complement system).{{cite journal | vauthors = DiLillo DJ, Tan GS, Palese P, Ravetch JV | title = Broadly neutralizing hemagglutinin stalk-specific antibodies require FcγR interactions for protection against influenza virus in vivo | journal = Nature Medicine | volume = 20 | issue = 2 | pages = 143–51 | date = February 2014 | pmid = 24412922 | pmc = 3966466 | doi = 10.1038/nm.3443 }}

The stem or stalk region of HA (HA2), is highly conserved across different strains of influenza viruses. The conservation makes it an attractive target for broadly neutralizing antibodies that target all flu subtypes, and for developing universal vaccines that let humans produce these antibodies naturally.{{cite journal | vauthors = Sautto GA, Kirchenbaum GA, Ross TM | title = Towards a universal influenza vaccine: different approaches for one goal | journal = Virology Journal | volume = 15 | issue = 1 | pages = 17 | date = January 2018 | pmid = 29370862 | pmc = 5785881 | doi = 10.1186/s12985-017-0918-y | doi-access = free }} Its structural changes from prefusion to postfusion conformation drives fusion between viral membrane and host membrane. Therefore, antibodies targeting this region can block key structural changes that eventually drive the membrane fusion process, and therefore are able to achieve antiviral activity against several influenza virus subtypes. At least one fusion-inhibiting antibody was found to bind closer to the top of hemagglutinin, and is thought to work by cross-linking the heads together, the opening of which is thought to be the first step in the membrane fusion process.{{cite journal | vauthors = Barbey-Martin C, Gigant B, Bizebard T, Calder LJ, Wharton SA, Skehel JJ, Knossow M | title = An antibody that prevents the hemagglutinin low pH fusogenic transition | journal = Virology | volume = 294 | issue = 1 | pages = 70–4 | date = March 2002 | pmid = 11886266 | doi = 10.1006/viro.2001.1320 | doi-access = free }}

Examples are human antibodies F10,{{cite journal | vauthors = Sui J, Hwang WC, Perez S, Wei G, Aird D, Chen LM, Santelli E, Stec B, Cadwell G, Ali M, Wan H, Murakami A, Yammanuru A, Han T, Cox NJ, Bankston LA, Donis RO, Liddington RC, Marasco WA | title = Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses | journal = Nature Structural & Molecular Biology | volume = 16 | issue = 3 | pages = 265–73 | date = March 2009 | pmid = 19234466 | pmc = 2692245 | doi = 10.1038/nsmb.1566 }} FI6,{{cite journal | vauthors = Corti D, Voss J, Gamblin SJ, Codoni G, Macagno A, Jarrossay D, Vachieri SG, Pinna D, Minola A, Vanzetta F, Silacci C, Fernandez-Rodriguez BM, Agatic G, Bianchi S, Giacchetto-Sasselli I, Calder L, Sallusto F, Collins P, Haire LF, Temperton N, Langedijk JP, Skehel JJ, Lanzavecchia A | title = A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins | journal = Science | volume = 333 | issue = 6044 | pages = 850–6 | date = August 2011 | pmid = 21798894 | doi = 10.1126/science.1205669 | bibcode = 2011Sci...333..850C | s2cid = 5086468 }} CR6261. They recognize sites in the stem/stalk region (orange region in figure at right), far away from the receptor binding site.{{cite journal | vauthors = Throsby M, van den Brink E, Jongeneelen M, Poon LL, Alard P, Cornelissen L, Bakker A, Cox F, van Deventer E, Guan Y, Cinatl J, ter Meulen J, Lasters I, Carsetti R, Peiris M, de Kruif J, Goudsmit J | title = Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells | journal = PLOS ONE| volume = 3 | issue = 12 | pages = e3942 | year = 2008 | pmid = 19079604 | pmc = 2596486 | doi = 10.1371/journal.pone.0003942 | bibcode = 2008PLoSO...3.3942T | doi-access = free }}{{cite journal | vauthors = Ekiert DC, Bhabha G, Elsliger MA, Friesen RH, Jongeneelen M, Throsby M, Goudsmit J, Wilson IA | title = Antibody recognition of a highly conserved influenza virus epitope | journal = Science | volume = 324 | issue = 5924 | pages = 246–51 | date = April 2009 | pmid = 19251591 | pmc = 2758658 | doi = 10.1126/science.1171491 | bibcode = 2009Sci...324..246E }}

In 2015 researchers designed an immunogen mimicking the HA stem, specifically the area where the antibody ties to the virus of the antibody CR9114. Rodent and nonhuman primate models given the immunogen produced antibodies that could bind with HAs in many influenza subtypes, including H5N1.{{cite web|url=http://www.zmescience.com/ecology/world-problems/effective-flu-vaccines-2788324|title=Universal flu vaccine: research moves closer| vauthors = Micu A |date=2015-08-25|website=ZME Science|access-date=2016-06-10}} When the HA head is present, the immune system does not generally make bNAbs (broadly neutralizing antibodies). Instead, it makes the head antibodies that only recognize a few subtypes. Since the head is responsible for holding the three HA units together, a stem-only HA needs its own way to hold itself together. One team designed self-assembling HA-stem nanoparticles, using a protein called ferritin to hold the HA together. Another replaced and added amino acids to stabilize a mini-HA lacking a proper head.{{citation needed|date=August 2022}}

A 2016 vaccine trial in humans found many broadly neutralizing antibodies targeting the stem produced by the immune system. Three classes of highly similar antibodies were recovered from multiple human volunteers, suggesting that a universal vaccine that produces reproducible antibodies is indeed possible.{{cite journal | vauthors = Joyce MG, Wheatley AK, Thomas PV, Chuang GY, Soto C, Bailer RT, Druz A, Georgiev IS, Gillespie RA, Kanekiyo M, Kong WP, Leung K, Narpala SN, Prabhakaran MS, Yang ES, Zhang B, Zhang Y, Asokan M, Boyington JC, Bylund T, Darko S, Lees CR, Ransier A, Shen CH, Wang L, Whittle JR, Wu X, Yassine HM, Santos C, Matsuoka Y, Tsybovsky Y, Baxa U, Mullikin JC, Subbarao K, Douek DC, Graham BS, Koup RA, Ledgerwood JE, Roederer M, Shapiro L, Kwong PD, Mascola JR, McDermott AB | title = Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses | journal = Cell | volume = 166 | issue = 3 | pages = 609–623 | date = July 2016 | pmid = 27453470 | pmc = 4978566 | doi = 10.1016/j.cell.2016.06.043 | author43-link = John R. Mascola }}

There are also other hemagglutinin-targeted influenza virus inhibitors that are not antibodies:{{cite journal | vauthors = Zeng LY, Yang J, Liu S | title = Investigational hemagglutinin-targeted influenza virus inhibitors | journal = Expert Opinion on Investigational Drugs | volume = 26 | issue = 1 | pages = 63–73 | date = January 2017 | pmid = 27918208 | doi = 10.1080/13543784.2017.1269170 | s2cid = 11401818 }}

1. Arbidol
2. Small Molecules
3. Natural compounds
4. Proteins and peptides

{{Portal|Viruses}}

• FI6 antibody
• Phytohemagglutinin
• Hemagglutinin
• Neuraminidase
• Antigenic shift
• Sialic acid
• Epitope
• H5N1 genetic structure

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: [p] ^Hemagglutinin is pronounced /he-mah-Glue-tin-in/.{{cite web |title= Scientists race to develop a vaccine against a killer flu | vauthors = Boyd RS | work = Knight Ridder Newspapers |orig-year= 6 October 2005 |date= 24 May 2007 |url= http://www.mcclatchydc.com/latest-news/article24450214.html | via = Mcclatchydc.com |access-date= 2018-05-24 }}{{cite web |title= Bird flu: Don't fly into a panic – Harvard Health |url= https://www.health.harvard.edu/newsletter_article/Bird_flu_Dont_fly_into_a_panic |website= Harvard.edu |date= October 2006 |access-date= 2018-05-24 }}

{{refend}}

{{Reflist}}

• [https://web.archive.org/web/20090327234834/http://www.callutheran.edu/Academic_Programs/Departments/BioDev/omm/jmol/flu_div/start.html Jmol tutorial of influenza hemagglutinin structure and activity.]
• {{PDB Molecule of the Month|76|Hemagglutinin}} (April 2006)
• [http://www.fludb.org Influenza Research Database] Database of influenza protein sequences and structures
• [http://www.pdbe.org/emsearch/hemagglutinin* 3D macromolecular structures of influenza hemagglutinin from the EM Data Bank(EMDB)]
• {{PDBe-KB2|K7N5L2|Influenza A virus Hemagglutinin}}
• {{PDBe-KB2|A0A0J9X268|H6N1 subtype Hemagglutinin}}
• {{PDBe-KB2|A0A0J9X267|H6N1 subtype Hemagglutinin HA2 chain}}

{{Viral proteins}}

{{DEFAULTSORT:Hemagglutinin (Influenza)}}

Category:Influenza A virus

Category:Viral structural proteins