Hemagglutinin (influenza)

Influenza hemagglutinin (HA) or haemagglutinin^[p] (British English) is a homotrimeric glycoprotein found on the surface of influenza viruses and is integral to its infectivity.

Hemagglutinin is a

The name "hemagglutinin" comes from the protein's ability to cause red blood cells (erythrocytes) to clump together ("agglutinate") in vitro.^[4]

Subtypes

Hemagglutinin (HA) in influenza A has at least 18 different subtypes. These subtypes are named H1 through H18. H16 was discovered in 2004 on influenza A viruses isolated from black-headed gulls from Sweden and Norway. H17 was discovered in 2012 in fruit bats.^[5][6] Most recently, H18 was discovered in a Peruvian bat in 2013.^[7] The first three hemagglutinins, H1, H2, and H3, are found in human influenza viruses. By phylogenic 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.^[8] The serotype of influenza A virus is determined by the Hemagglutinin (HA) and Neuraminidase (NA) proteins present on its surface.^[9] Neuraminidase (NA) has 11 known subtypes, hence influenza virus is named as H1N1, H5N2 etc., depending on the combinations of HA and NA.^{[citation needed]}

A highly pathogenic avian flu virus of

HA1

HA1 is mostly composed of antiparallel beta-sheets.[14]

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).^[20]

Function

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.^[21]

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.^[22] 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]}

This so-called "

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.^[26] 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.^[27]

Examples are human antibodies F10,^[28] FI6,^[29] CR6261. They recognize sites in the stem/stalk region (orange region in figure at right), far away from the receptor binding site.^[30][31]

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.^[32] 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]}

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.^[33]

Other agents

There are also other hemagglutinin-targeted influenza virus inhibitors that are not antibodies:^[34]

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

See also

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

Notes

References