Influenza hemagglutinin H3

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Influenza hemagglutinin (H3 serotype) was the first glycoprotein structure to be solved at atomic resolution, by Ian Wilson, John Skehel and Don Wiley in 1981. The collaboration between the Skehel and Wiley labs provided great insight into hemagglutinin function, and it remains the prototype for understanding receptor recognition, antigenic variation, and the extraordinary conformational changes associated with target membrane insertion and ultimately fusion of viral with cell membrane to allow the viral genome to enter the cell and replicate.

In the 1980s the Paulson lab made the seminal discovery that human and avian viruses with the H3 serotype have different receptor specificities; that human viruses bind to Neu5Acα2-6Gal while avian viruses bind Neu5Acα2-3Gal. In two very elegant experiments they were able to switch these specificities by applying selective pressure, and showed that a single amino acid change (L226Q) was all that was required for early H3N2 viruses to switch between human and avian specificities. These results showed how easy it can be for avian viruses to cross the species barrier into humans. Seasonal influenza viruses with the H3 serotype continue to circulate in the human population, and subtleties in their receptor specificities appear to be playing a role in how clinical isolates can be recovered in laboratory hosts. CFG investigators are using tools provided by the CFG to analyze the detailed receptor specificity of the circulating H3N2 influenza viruses and their interaction with laboratory hosts to better understand this phenomenon, which has direct consequences on production of vaccines.

Although the influenza H3 hemagglutinin has been chosen as the paradigm, since so much is known, there are 16 subtypes of influenza HA (H1-H16), defined by lack of antigenic cross-reactivity. There is typically only about 20% amino acid sequence identity between HAs of different subtypes. There are interesting and important differences in how easily a particular strain within the subtype can change its binding specificity between avian-like and human-like receptors, leading to the failure of H5N1 to be established in the human population while swine-origin H1N1 showed high transmissibility between humans from the time it was first isolated.

To understand the transmission of influenza viruses and how new pandemics begin, it will be important to study a variety of HA subtypes and strains. but for other subtypes the rules are different and are not yet understood. The H5N1 avian virus has still not acquired the ability to transmit between humans, despite at least 15 years of opportunity. The CFG has facilitated considerable advances in our knowledge of the role of sialic acid binding in influenza host specificity and tropism for the upper or lower respiratory tract, and these studies need to be continued until we understand how influenza viruses enter the human population to cause each new pandemic, and the role of receptor specificity in pathogenicity.


CFG Participating Investigators contributing to the understanding of this paradigm

CFG Participating Investigators (PIs) contributing to the understanding of H3 include: Gillian Air, Rafi Ahmed, Nicolai Bovin, Ruben Donis, Chwan-Chuen King, Vladimir Lugovtsev, Christopher Olsen, Peter Palese, James Paulson, Andrew Pekosz, Daniel Perez, Peter P.J.M. Rottier, Charles Russell, Ram Sasisekharan, Dorothy Scott, David Smith, James Stevens, Stephen Mark Tompkins, Reinhard Vlasak, Qinghua Wang, Ian Wilson

Progress toward understanding this GBP paradigm

Carbohydrate ligands

Ligands for H3 hemagglutinin are sialylated glycans. The H3 hemagglutinin of human viruses (subtypeH3N2) binds to N-acetylneuraminic acid linked &alpha2-6 to galactose, sometimes N-acetylgalactosamine. Recent human H3 HAs have shown variation in their specificity of binding downstream sugars[1]

Cellular expression

HA is expressed on the surface of influenza virus infected cells before being budded out into progeny virions. H3N2 viruses infect the respiratory tract of humans and birds; in birds they may also infect the gut epithelia. H3N2 viruses infect very few continuous cell lines. Madin-Darby canine kidney cells are most commonly used. Non-permissive cell lines may take up virus efficiently, replicate RNA and express HA on the cell surface but do not bud new virus particles [2]


Biological roles of GBP-ligand interaction

CFG resources used in investigations

The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for "hemagglutinin".

Glycan profiling

Glycogene microarray

Knockout mouse lines

Glycan array

The majority of PI-initiated requests for CFG resources to study influenza have been requests for analysis of receptor specificity on the glycan array, and the remainder have been requests for compounds to conduct in vitro assays in investigators laboratories. In addition, the CFG glycan array library has been used for custom sialic acid glycan array to the U.S. Centers for Disease Control (CDC) for analysis of the receptor specificity of emerging viruses, with data deposited to the CFG database.

Related GBPs

Influenza virus HAs of other serotype H1, H2, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16 and type B. Type A subtypes H1, H2, H5, H6, H7, and H9 are all being actively investigated by CFG investigators for their potential to jump to humans and type B for its failure to spread in non-human species.


  1. Gulati S, Smith DF, Air GM. Deletions of neuraminidase and resistance to oseltamivir may be a consequence of restricted receptor specificity in recent H3N2 influenza viruses. Virology J 2009;6(22).
  2. Kumari K, Gulati S, Smith DF, Gulati U, Cummings RD, Air GM. Receptor binding specificity of recent human H3N2 influenza viruses. Virol J 2007;4(42):1-12.


The CFG is grateful to the following PIs for their contributions to this wiki page: Gillian Air, James Paulson

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