Immunology - Variation and infectivity neutralization in influenza

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</td><td class="maintextright" align="right" nowrap="nowrap"> View/Print PDF article (928K)</td></tr></tbody></table></td></tr><tr><td colspan="2" class="maintextleft">Download to citation manager</td></tr><tr><td colspan="2" class="maintextleft">Order Permissions</td></tr><tr><td colspan="2" class="maintextleft">Alert me when this article is cited | Atom | RSS (What is RSS?)</td></tr><tr><!-- journal info --><td colspan="2"><hr align="center" noshade="noshade" size="1">Immunology
Volume 119 Page 1 - September 2006
doi:10.1111/j.1365-2567.2006.02421.x</td><!-- /journal info --></tr><tr><td colspan="2">Volume 119 Issue 1

<table><tbody><tr><td colspan="2" class="maintextleft">Received 29 March 2006; accepted 19 May 2006.
</td></tr><tr><td><hr align="center" noshade="noshade" size="1"></td></tr><tr><td colspan="2" class="maintextleft">Published article online 20 Jul 2006
Issue online 20 Jul 2006</td></tr><tr><td>
</td></tr><tr><td class="maintextbldleft">Affiliations
</td></tr><tr><td class="maintextleft">¹CNRS Laboratoire d'Enzymologie et Biochimie Structurales, Gif sur Yvette Cedex, France, and ²MRC National Institute for Medical Research, London, UK
</td></tr><tr><td>
</td></tr><tr><td class="maintextbldleft">Correspondence
</td></tr><tr><td class="maintextleft">Dr John Skehel, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Email: <nobr>mbrenna@nimr.<wbr>mrc.<wbr>ac.<wbr>uk</nobr>
Senior author: Dr John Skehel</td></tr></tbody></table>
</td></tr><tr><td colspan="2" height="11"> </td></tr><!-- abstract content --><tr><td colspan="2"> </td></tr><tr><td colspan="2" class="abstracttitle">REVIEW ARTICLE</td></tr><tr><td colspan="2" class="abstracttitle">Variation and infectivity neutralization in influenza</td></tr><tr><td colspan="2" class="maintextleftinclined">Marcel Knossow¹ and John J. Skehel²</td></tr><tr><td colspan="2" class="document-summary"><table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td class="maintextbldleft" bgcolor="#99ccff" height="16" nowrap="nowrap" width="150"> Summary</td></tr></tbody></table>Worldwide epidemics of influenza are caused by viruses that normally infect other species, particularly waterfowl, and that contain haemagglutinin membrane glycoproteins (HAs) to which the human population has no immunity. Anti-HA immunoglobulins neutralize influenza virus infectivity. In this review we outline structural differences that distinguish the HAs of the 16 antigenic subtypes (H1?16) found in viruses from avian species. We also describe structural changes in HA required for the effective transfer to humans of viruses containing three of them, H1, H2 and H3, in the 1918 (Spanish), the 1957 (Asian) and the 1968 (Hong Kong) pandemics, respectively. In addition, we consider changes that may be required before the current avian H5 viruses could pass from human to human.
</td></tr><!-- /abstract content --><!-- fulltext content --><tr><td colspan="2" class="document-body"><table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td class="maintextbldleft" bgcolor="#99ccff" height="16" nowrap="nowrap" width="150"> Introduction</td><td class="maintextright" bgcolor="#99ccff" height="16" nowrap="nowrap" width="62">Go to:</td><td class="fulltextdmenu" align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="92"><select name="select23" class="fulltextdmenu" onchange="GoTo(this, 'self')"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="">Introduction <<</option><option value="#h5">HA structure</option><option value="#h6">Sialic acid receptor bind...</option><option value="#h7">Antigenic variation</option><option value="#h8">Escape from infectivity-n...</option><option value="#h9">Antigenic variation in re...</option><option value="#h10">The mechanism for neutral...</option><option value="#h11">The number of antibodies ...</option><option value="#h12">Conclusions</option><option value="#h13">Acknowledgements</option><option value="#h14">References</option><option value="#h1">Abbreviations: </option></select></td><td align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="10"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="32"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="16"></td><td bgcolor="#ffffff" height="16" nowrap="nowrap" width="10"></td></tr></tbody></table>Following pandemics, viruses of the previously circulating subtype (H1 after 1957 and H2 after 1968) were eliminated by unknown mechanisms, but epidemics caused by infections with antigenic variants of the new pandemic viruses continued to occur. These variants are selected under immune pressure provided by antibodies that block the HA function of sialic acid receptor binding, the first step in virus infection. We describe the structural basis of these blocks on H3 subtype HAs from viruses isolated in epidemics since 1968 by comparison with the structures and infectivity-neutralizing activities of three monoclonal antibodies (mAbs) that we have studied in detail, and we show how this information sheds light on the mechanism of antibody neutralization of virus infectivity.
<table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td class="maintextbldleft" bgcolor="#99ccff" height="16" nowrap="nowrap" width="150"> HA structure</td><td class="maintextright" bgcolor="#99ccff" height="16" nowrap="nowrap" width="62">Go to:</td><td class="fulltextdmenu" align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="92"><select name="select23" class="fulltextdmenu" onchange="GoTo(this, 'self')"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#h4">Introduction</option><option value="">HA structure <<</option><option value="#h6">Sialic acid receptor bind...</option><option value="#h7">Antigenic variation</option><option value="#h8">Escape from infectivity-n...</option><option value="#h9">Antigenic variation in re...</option><option value="#h10">The mechanism for neutral...</option><option value="#h11">The number of antibodies ...</option><option value="#h12">Conclusions</option><option value="#h13">Acknowledgements</option><option value="#h14">References</option><option value="#h1">Abbreviations: </option></select></td><td align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="10"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="32"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="16"></td><td bgcolor="#ffffff" height="16" nowrap="nowrap" width="10"></td></tr></tbody></table>HAs are trimers of identical subunits, each of which consists of a virus membrane-proximal, α-helix-rich stem-like structure that supports a membrane-distal globular domain (Fig. 1).^1,2 HAs are placed into one of 16 antigenic subtypes on the basis of their ability to react with subtype-specific anti-HA hyperimmune sera.³⁵ This classification is reinforced by amino acid sequence comparisons, which indicate 40?80% sequence identity between subtypes and ≈ 90% identity within subtypes.⁶ Phylogenetically, the 16 subtypes form five clades that fall into two groups: one containing three clades and the other containing two clades.^6,7 Structurally, HAs representative of the five clades are distinguished by differences in the orientation of their membrane-distal globular domains relative to the central trimeric coiled-coil.^8,9 These differences in structure are related to differences in the conformation of the N-terminal region of the central coiled-coil and in the interactions it makes with the membrane distal globular domain. As a result, the membrane distal domains of HAs of the clade represented by the H3 HA are twisted clockwise by ≈ 6? in relation to those of the clade represented by H7 HA in the same group; the membrane-distal domains of clades represented by H1, H9 and H13 HAs in the other group, by contrast, are twisted through 30?, 19? and 16?, respectively, in similar comparisons with H7 HA (Fig. 1).^9,10 It has been noted that this major structural distinction, and a number of other clade-specific structural differences, are in regions of the HAs that refold in membrane fusion,^9,11,¹² and it has been suggested that this common feature may have a role in the evolution of influenza viruses.^8,9 The structural basis for intersubtype antigenic differences involved in subtype definition is unclear from current analyses of the structures of different HAs.



Figure 1. The structure of influenza haemagglutinin membrane glycoproteins (HAs). Left: top- and side-view of a ribbon diagram of the HA structure. Two monomers of the HA trimer are drawn in grey, one is coloured. Each monomer is synthesized as a single polypeptide chain that is post-translationally cleaved into two chains ? HA1 and HA2 ? which are shown in blue and red, respectively. Right: superposed ribbon diagrams of the receptor-binding domains of a clade 3 HA (represented by H1) and a clade 5 HA (represented by H7). Clades 1, 2 and 4 are represented by subtypes H9, H13 and H3, respectively.

<table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td class="maintextbldleft" bgcolor="#99ccff" height="16" nowrap="nowrap" width="150"> Sialic acid receptor binding</td><td class="maintextright" bgcolor="#99ccff" height="16" nowrap="nowrap" width="62">Go to:</td><td class="fulltextdmenu" align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="92"><select name="select23" class="fulltextdmenu" onchange="GoTo(this, 'self')"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#h4">Introduction</option><option value="#h5">HA structure</option><option value="">Sialic acid receptor bind... <<</option><option value="#h7">Antigenic variation</option><option value="#h8">Escape from infectivity-n...</option><option value="#h9">Antigenic variation in re...</option><option value="#h10">The mechanism for neutral...</option><option value="#h11">The number of antibodies ...</option><option value="#h12">Conclusions</option><option value="#h13">Acknowledgements</option><option value="#h14">References</option><option value="#h1">Abbreviations: </option></select></td><td align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="10"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="32"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="16"></td><td bgcolor="#ffffff" height="16" nowrap="nowrap" width="10"></td></tr></tbody></table>HAs mediate the first stages of virus infection, sialic acid receptor binding and virus membrane?cell membrane fusion.^1,2 The receptor-binding sites in all HAs are at the membrane distal tip of each subunit in the trimer.¹³¹⁵ They contain the conserved amino acids ? Y98, W153, H183 and Y195 ? that form the base of the site which is limited at the top by a short α-helix (the 190-helix, residues 190?198), a loop-like structure at the front edge (the 130-loop, residues 133?138) and another loop that forms the left edge, near the intersubunit interface (the 220-loop, residues 220?229) (Fig. 2).
The α-anomeric sialic acid components of receptor analogues in crystalline complexes with HAs make interactions between Y98 and the sialic acid 8-OH, peptide carbonyl 135 and N of the sialic acid acetamido substituent, S/T 136 and the sialic acid carboxylate, and between peptide amide 137 and the carboxylate.¹⁵²¹ HAs of avian viruses prefer α2,3-linked sialic acids^22,23 in a trans conformation about the glycosidic linkage.¹⁹ In this conformation, the glycosidic oxygen of the α2,3 linkage is directed towards the base of the site, and conserved Q226 forms a hydrogen bond with the 4-OH of Gal2 of the oligosaccharide receptor. HAs of human viruses, by contrast, preferentially bind sialic acid in α2,6-linkage to galactose,²² in a cis conformation about the glycosidic oxygen.^18,19 In this conformation, the glycosidic oxygen is oriented towards solution with C-6 of Gal2 directed into the site. In H2 and H3 subtype HAs of the 1957 and 1968 pandemics, binding of receptors in this conformation required substitution of Q226 of avian HA precursors by L226 in the human virus HAs.²⁴ In the H1 HAs of the 1918 pandemic era, however, Q226 of the avian precursor was retained,⁶ adopting a lower position in the site and avoiding contact with C-6 of Gal2 and the lower surface of the Gal2 ring.²⁰ Analyses of the HAs of H5 avian viruses, similar to those of viruses that have recently infected humans in the Far East, indicate that like all avian HAs they prefer α2,3-linked sialic acid.^19,25 Comparing them with H1, H2 and H3 HAs from human viruses suggests that a similar mutation of Q226L, which occurred in H2 and H3 HAs, would be required for effective binding of H5 HA to α2,6-linked receptors.²⁶ The lack of effective interhuman transfer to date, despite sufficient virus replication to cause mortality and serious morbidity in humans,^27,28 is presumed (at least in part) to relate to these differences in receptor preference.



Figure 2. The haemagglutinin membrane glycoprotein (HA) receptor-binding site. Left: side-view of HA (same colour code as in Figure 1), with the receptor-binding site of one monomer highlighted. Top right: sialic acid (yellow) and residue side-chains and main-chain atoms that interact with it are presented as ball-and-stick models. Hydrogen bonds are presented as dashed lines. Bottom right: overview of sialic acid in α2,3- and α2,6-linkages to galactose bound to avian H3 and human H3 (left and right panels, respectively). In these views, the only side-chain presented is that of residue 226 of HA1.

<table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td class="maintextbldleft" bgcolor="#99ccff" height="16" nowrap="nowrap" width="150"> Antigenic variation</td><td class="maintextright" bgcolor="#99ccff" height="16" nowrap="nowrap" width="62">Go to:</td><td class="fulltextdmenu" align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="92"><select name="select23" class="fulltextdmenu" onchange="GoTo(this, 'self')"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#h4">Introduction</option><option value="#h5">HA structure</option><option value="#h6">Sialic acid receptor bind...</option><option value="">Antigenic variation <<</option><option value="#h8">Escape from infectivity-n...</option><option value="#h9">Antigenic variation in re...</option><option value="#h10">The mechanism for neutral...</option><option value="#h11">The number of antibodies ...</option><option value="#h12">Conclusions</option><option value="#h13">Acknowledgements</option><option value="#h14">References</option><option value="#h1">Abbreviations: </option></select></td><td align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="10"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="32"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="16"></td><td bgcolor="#ffffff" height="16" nowrap="nowrap" width="10"></td></tr></tbody></table>Examination of the sites of amino acid substitution in natural variants of HA from H3 subtype viruses that were isolated during the 1968?2005 period of the Hong Kong pandemic shows that they are scattered throughout the molecule (Fig. 3a).^2,2936 Most of the changes retained in HAs of viruses isolated in subsequent years, namely the 'fixed' changes, involved residues on the surface of HA, whereas about two-thirds of those not retained were found to be buried.^1,2 This suggests that the 'fixed' substitutions (Fig. 3b) have been selected because they prevent antibody binding and this suggestion is supported by the coincidence of the locations of these substitutions with the locations of amino acid substitutions detected in antigenic variant HAs selected by growing virus in the presence of monoclonal anti-HA (Fig. 3c).³¹ Similar observations to these have been made with H1 subtype viruses and mutants selected with mAbs.^37,38
The sites of mAb-selected mutations indicate the sites at which the selecting antibodies bind. This was initially concluded from electron micrographs of HA?antibody complexes in which the locations of antibody-binding sites and the sites of amino acid substitutions in variant HAs coincide.³⁹ Further support was provided by X-ray crystallography of antibody-selected mutant HAs, which all showed only local changes in HA structure at the sites of the amino acid substitution and therefore defined the regions recognized by the antibodies.^17,40,⁴¹ Subsequently, these conclusions were verified by studies of the structures of complexes of mAb Fabs with HA (Fig. 4).⁴²⁴⁵


Figure 3. Distribution of sequence changes in haemagglutinin membrane glycoproteins (HAs) of the Hong Kong pandemic era during the 1968?2005 period. The space-filling models represent, in yellow, the virus receptor-binding site and, in green, substituted amino acids. (a) All substitutions in HAs of viruses isolated between 1968 and 2005; (b) amino acid substitutions that were retained in subsequent years; (c) amino acid substitutions detected in monoclonal antibody-selected variants of A/Hong Kong/68 HA. The α-carbon tracings of the HA trimers are coloured blue and red to denote the HA1 and HA2 polypeptide chains that form each subunit of the trimer.

<table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td class="maintextbldleft" bgcolor="#99ccff" height="16" nowrap="nowrap" width="150"> Escape from infectivity-neutralizing antibodies</td><td class="maintextright" bgcolor="#99ccff" height="16" nowrap="nowrap" width="62">Go to:</td><td class="fulltextdmenu" align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="92"><select name="select23" class="fulltextdmenu" onchange="GoTo(this, 'self')"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#h4">Introduction</option><option value="#h5">HA structure</option><option value="#h6">Sialic acid receptor bind...</option><option value="#h7">Antigenic variation</option><option value="">Escape from infectivity-n... <<</option><option value="#h9">Antigenic variation in re...</option><option value="#h10">The mechanism for neutral...</option><option value="#h11">The number of antibodies ...</option><option value="#h12">Conclusions</option><option value="#h13">Acknowledgements</option><option value="#h14">References</option><option value="#h1">Abbreviations: </option></select></td><td align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="10"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="32"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="16"></td><td bgcolor="#ffffff" height="16" nowrap="nowrap" width="10"></td></tr></tbody></table>mAb-selected mutants escape neutralization by the selecting antibody.^46,47 The antibodies still bind to the mutant HAs, but with a much reduced affinity; for example, the Fab of antibody 1 in Fig. 4 binds escape mutants with affinities between K_D 4 ? 10⁶ m and 5 ? 10⁷ m, significantly lower than its affinity for wild-type HA (K_D 10⁹ m).⁴¹ Such reductions in antibody affinity for the selected variant are the essential consequences of antigenically significant amino acid substitutions.
Most mAb-selected antigenic variants of HA contain single amino acid substitutions.^31,37,48,49 In selected variants, as well as in H3 HAs of viruses isolated during the 1968?2005 period, there appears to be no general preference for replacement of an amino acid by a larger or by a differently charged side-chain; in one of the mAb-selected mutants, the amino acid substitution that resulted in the largest decrease in antibody affinity was isosteric (T131I).⁴¹ Oligosaccharide attachment was also found to prevent antibody recognition. This is presumably achieved in two ways: protein surfaces covered by carbohydrate side-chains are thought not to induce antibodies; and because the carbohydrate side-chains themselves are synthesized by cellular enzymes, they are antigenically 'self'. Consistent with these proposals, the surfaces of the Hong Kong pandemic HAs, covered by the carbohydrate attached at N165, for example, are invariant, whereas the equivalent region in H1 HAs that lack carbohydrate are not.^31,37 Novel oligosaccharide attachment can also contribute to antigenic variation. This was demonstrated experimentally using a mAb-selected variant HA that had a new oligosaccharide attachment site. When synthesized in the presence of tunicamycin to block glycosylation, the variant reverted to binding the antibody that had been used to select it.^50,51 Since the beginning of the Hong Kong pandemic period in 1968 there has been an increase in the number of oligosaccharide attachment sites specifically on the membrane distal domain of HA; the HA of the 1968 Hong Kong virus contained three attachment sites at positions 81, 165 and 285, and by 2005 this number had increased to eight, at positions 63, 122, 126, 133, 144, 165, 246 and 285.⁵²


Figure 4. Neutralizing antibody Fab?haemagglutinin membrane glycoprotein (HA) complexes. Ribbon diagrams of the complexes showing one A/Hong Kong/68 HA monomer and, from left to right, Fabs (in green) of antibody 1, antibody 2 and antibody 3 which select mutations at HA1 residues 157, 226 and 63, respectively. These residues are coloured red in the complexes. Amino acids in the receptor-binding site are shown as yellow space-filling models.

<table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td class="maintextbldleft" bgcolor="#99ccff" height="16" nowrap="nowrap" width="150"> Antigenic variation in relation to HA functions</td><td class="maintextright" bgcolor="#99ccff" height="16" nowrap="nowrap" width="62">Go to:</td><td class="fulltextdmenu" align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="92"><select name="select23" class="fulltextdmenu" onchange="GoTo(this, 'self')"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#h4">Introduction</option><option value="#h5">HA structure</option><option value="#h6">Sialic acid receptor bind...</option><option value="#h7">Antigenic variation</option><option value="#h8">Escape from infectivity-n...</option><option value="">Antigenic variation in re... <<</option><option value="#h10">The mechanism for neutral...</option><option value="#h11">The number of antibodies ...</option><option value="#h12">Conclusions</option><option value="#h13">Acknowledgements</option><option value="#h14">References</option><option value="#h1">Abbreviations: </option></select></td><td align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="10"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="32"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="16"></td><td bgcolor="#ffffff" height="16" nowrap="nowrap" width="10"></td></tr></tbody></table>The main common characteristic of the sites of amino acid substitutions in natural and antibody-selected antigenic variants is that they are on the surface of the membrane-distal globular domain of HA, probably because this is the part of the protein most accessible to antibodies on the tightly packed viral surface.⁵³ Many of these sites surround the receptor-binding site, which suggests a relationship between neutralization of viral infectivity and prevention of virus binding to cells.^15,18,³¹ This raises questions of whether antibodies against the receptor-binding site exist and, if they do, of how viruses might escape neutralization by these antibodies. A number of mAbs contact amino acid residues that are components of the receptor-binding site (Fig. 4).^41,42 However, comparison of the sizes of the receptor-binding site (≈ 800 ?²),¹⁵ and of antibody?antigen interfaces (between 1200 and 1500 ?²),^54,55 indicates that 'antibody footprints' are larger and therefore antibodies that interact with the receptor-binding site would also cover HA residues that are not involved in binding to receptor. Mutations at these positions would allow virus to escape from neutralization without imposing selective pressure on residues of the receptor-binding site that could compromise its activity. Support for these conclusions is provided by the findings that the receptor-binding site is formed by conserved residues^15,16,¹⁸ and that all the mutations which allow the virus to escape from neutralization by antibodies that partially overlap the receptor-binding site are at positions outside the site.⁴²
<table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td class="maintextbldleft" bgcolor="#99ccff" height="16" nowrap="nowrap" width="150"> The mechanism for neutralization of infectivity by antibodies</td><td class="maintextright" bgcolor="#99ccff" height="16" nowrap="nowrap" width="62">Go to:</td><td class="fulltextdmenu" align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="92"><select name="select23" class="fulltextdmenu" onchange="GoTo(this, 'self')"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#h4">Introduction</option><option value="#h5">HA structure</option><option value="#h6">Sialic acid receptor bind...</option><option value="#h7">Antigenic variation</option><option value="#h8">Escape from infectivity-n...</option><option value="#h9">Antigenic variation in re...</option><option value="">The mechanism for neutral... <<</option><option value="#h11">The number of antibodies ...</option><option value="#h12">Conclusions</option><option value="#h13">Acknowledgements</option><option value="#h14">References</option><option value="#h1">Abbreviations: </option></select></td><td align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="10"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="32"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="16"></td><td bgcolor="#ffffff" height="16" nowrap="nowrap" width="10"></td></tr></tbody></table>Protection against influenza is mediated by anti-HA immunoglobulins which neutralize virus infectivity in vitro and in vivo.^56,57 There have, however, been uncertainties about the mechanisms involved in neutralization. In quantitative studies of infectivity neutralization we used three anti-1968 Hong Kong HA mAbs that we also used in structural studies (Fig. 4). We observed that reductions in the amount of virus bound to cells, and in the number of infectious particles produced following infection, co-vary directly with antibody concentration (Fig. 5).⁵³ From these observations, inhibition of virus binding to cells appears to be the mechanism by which these antibodies neutralize virus infectivity. Two additional observations with these antibodies are consistent with this. Two of the antibodies bind to the receptor-binding site (antibodies 1 and 2, Fig. 4) and have affinities for HA (K_D of Fabs 5 ? 10¹⁰ m and 1?7 ? 10¹⁰ m) that are much higher than the affinities of the receptor-binding site for receptor analogues (K_D 2 ? 10³ m).¹⁶ As both antibodies contact three conserved residues in the receptor-binding site, they directly block receptor binding (Fig. 4). The third antibody (antibody 3, Fig. 4) which binds below the receptor-binding site⁴³ neutralizes less efficiently. As the shortest distance between a Fab atom of antibody 3 and a receptor-binding site atom is 17 ?, this antibody does not directly prevent the binding of receptor analogues to HA. However, in projecting over 50 ? from the virus surface, it sterically hinders the interaction between the HA to which it is bound and cellular receptors.
Because of the low affinity of HA for receptors (K_D 2 ? 10³ m), several HAs are required to bind to receptors in order to attach a virus particle to a cell.¹⁶ All three antibodies would prevent this simultaneous binding. Antibody 2 additionally prevents the HA structural transition that is required for virus and cellular membrane fusion^11,58 and therefore, in vitro, blocks fusion.⁴⁴ As in vivo fusion in endosomes follows receptor binding, for inhibition of fusion to contribute to neutralization it would have to be effective at an antibody concentration at which virus was not prevented from binding to cells. In this case, this would have to be below an antibody concentration of 5 ? 10¹⁰ m. At this concentration, one antibody is bound per five HA spikes, and the proportion of HA trimers internally cross-linked by antibodies is also 1 : 5. This means that ≈ 80% of the haemagglutinins could still undergo the low-pH structural change. It is possible therefore that if virus?antibody complexes, such as uncomplexed viruses, are taken into cells by endocytosis, and if a number of HAs need to co-operate to promote fusion, the impairment of the endosomal pH-activated structural transition of one in five HAs might prevent fusion. Because of the direct correlation between inhibition of binding to cells and neutralization of infectivity, however, this does not appear to be the case.
The three antibodies we have studied represent the variety of neutralizing antibodies that react with HA: two of them overlap with the receptor-binding site, while the third does not; one of the antibodies blocks the structural transition required for fusion, whereas the other two do not.⁵³ All three neutralize infectivity by preventing virus from binding to cells and we conclude that this is the mechanism used, by most protecting antibodies, to neutralize infectivity. However, a mechanism for neutralization in which a number of antibody molecules are required to prevent virus binding to cells has been considered incompatible with observations that neutralization appears to follow single-hit kinetics. The clearest evidence suggestive of single-hit kinetics is provided when incubation of virus with antibody leads to a linear variation of the logarithm of infectivity in relation to the number of antibodies bound per virus particle. In the case of influenza virus, this has been taken to imply that the binding of one antibody to a critical site on the virus abolishes infectivity.⁵⁹ Model calculations, however, show that the assumption that each antibody decreases the infectivity of a virus particle by a fixed fraction also leads to a close to linear variation of log (infectivity) as a function of the number of bound antibodies.⁶⁰ Given the accuracy of experimental neutralization kinetic data, the two mechanisms cannot be discriminated. Observations of apparent single-hit kinetics do not therefore contradict the interpretation that neutralization of infectivity requires the binding of a number of antibodies, each of which decreases infectivity, as it makes virus binding to cells less likely.⁶¹


Figure 5. The relationship between inhibition of virus binding to cells by antibodies and neutralization. The ratios of the number of virus plaques to the number of plaques without antibody (plain lines, filled symbols), and the ratio of cell-bound virus to cell-bound virus without antibody (dashed lines, open symbols), are plotted on a semilogarithmic scale as a function of antibody concentration. The blue, green and red curves correspond to antibodies 1, 2 and 3, respectively.

<table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td class="maintextbldleft" bgcolor="#99ccff" height="16" nowrap="nowrap" width="150"> The number of antibodies required to neutralize infectivity</td><td class="maintextright" bgcolor="#99ccff" height="16" nowrap="nowrap" width="62">Go to:</td><td class="fulltextdmenu" align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="92"><select name="select23" class="fulltextdmenu" onchange="GoTo(this, 'self')"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#h4">Introduction</option><option value="#h5">HA structure</option><option value="#h6">Sialic acid receptor bind...</option><option value="#h7">Antigenic variation</option><option value="#h8">Escape from infectivity-n...</option><option value="#h9">Antigenic variation in re...</option><option value="#h10">The mechanism for neutral...</option><option value="">The number of antibodies ... <<</option><option value="#h12">Conclusions</option><option value="#h13">Acknowledgements</option><option value="#h14">References</option><option value="#h1">Abbreviations: </option></select></td><td align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="10"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="32"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="16"></td><td bgcolor="#ffffff" height="16" nowrap="nowrap" width="10"></td></tr></tbody></table>Discussions of the mechanism of virus neutralization have also included the proposal that viruses are neutralized when their surface is completely coated with antibodies. It is the case that the coating density required for neutralization is such that virus binding to cells is prevented, but this does not necessarily require saturation of the virus. For example, approximately twice as many molecules per virus particle of antibody 2 are required for saturation compared with neutralization. By contrast, antibodies 1 and 3 neutralize infectivity at the concentration at which they saturate the virus. These results are consistent with conclusions made from the structures of the HA?Fab complexes that the number of antibody complexes at which saturation occurs depends on the geometry of the particular complex.⁵³ Thus, whereas Fabs of antibody 2 extend within the space projected radially from the bound trimer, antibodies 1 and 3 bind on the side of the trimer and occupy more space on the viral surface than the trimer (Fig. 4). Consistent with the mechanism we propose, saturation by any antibody with the ability to neutralize infectivity occurs at a concentration higher than or equal to that required to prevent virus from binding to cells.
The antibody concentrations required to achieve neutralization (2 ? 10¹⁰ m for antibodies 1 and 2 and 10⁸ m for antibody 3) are those required to prevent virus binding to cells. They are much higher than expected from the affinities of the antibodies for viral HA (6 ? 10¹² m and 10¹⁰ m for antibodies 1 and 3, respectively). This suggests that as more antibody molecules are bound to a virus particle, their avidity for HA decreases. This is the result of an increase in crowding and the consequent steric hindrance of additional antibody binding to the viral surface.⁵³ The antibody concentration at which neutralization occurs is therefore a combined function of the necessary occupancy of antibodies on the virus and of the avidity of the antibody for HA at that degree of occupancy.
<table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td class="maintextbldleft" bgcolor="#99ccff" height="16" nowrap="nowrap" width="150"> Conclusions</td><td class="maintextright" bgcolor="#99ccff" height="16" nowrap="nowrap" width="62">Go to:</td><td class="fulltextdmenu" align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="92"><select name="select23" class="fulltextdmenu" onchange="GoTo(this, 'self')"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#h4">Introduction</option><option value="#h5">HA structure</option><option value="#h6">Sialic acid receptor bind...</option><option value="#h7">Antigenic variation</option><option value="#h8">Escape from infectivity-n...</option><option value="#h9">Antigenic variation in re...</option><option value="#h10">The mechanism for neutral...</option><option value="#h11">The number of antibodies ...</option><option value="">Conclusions <<</option><option value="#h13">Acknowledgements</option><option value="#h14">References</option><option value="#h1">Abbreviations: </option></select></td><td align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="10"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="32"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="16"></td><td bgcolor="#ffffff" height="16" nowrap="nowrap" width="10"></td></tr></tbody></table>The differences in extent of variation in HA by comparison with receptor-binding glycoproteins of other acute infectious agents are assumed to be related to the existence, in avian species, of a reservoir of influenza viruses that contains all 16 HA subtypes. From this reservoir, three times in the last century, new viruses were introduced to the human population directly by cross-species transfer or following genetic reassortment between an avian virus and an extant human virus. Following these pandemics, antigenic variation occurs under immune pressure and presumably could continue until the viability of the virus is compromised by effects on the receptor-binding function of the HA target, or until variation is limited in some other way. Mutations that introduce new sites for glycosylation, for example, may be important in this regard because unlike those antigenic sites at which multiple consecutive amino acid substitutions can be selected, the sites that are modified by glycosylation are not subsequently under immune pressure and are, comparatively, 'fixed'. Their accumulation may eventually limit the rate of antigenic variation.
The objectives of regularly collecting information on variation in HA are primarily to characterize epidemic viruses as an aid to vaccine component selection and perhaps eventually to establish the relative antigenic importance of variation at particular sites.⁵² Conceivably, such information might enable prediction of subsequent structural and antigenic changes. Neither identification of site dominance, nor the ability to predict change, has as yet been achieved.
In addition, the relationship between antigenicity and immunogenicity remains unclear. For example, our knowledge of the determinants of HA immunogenicity, or of other factors that lead to the induction of antibodies of the different ranges of specificity in different infected members of the population, is incomplete. It is nevertheless essential for an understanding of the pathway of antigenic drift and possibly also for attempts at effective vaccination of all sections of the population.
</td></tr><tr><td colspan="2"> </td></tr><tr><td colspan="2" class="document-body"><table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td class="maintextbldleft" bgcolor="#99ccff" height="16" nowrap="nowrap" width="150"> Acknowledgements</td><td class="maintextright" bgcolor="#99ccff" height="16" nowrap="nowrap" width="62">Go to:</td><td class="fulltextdmenu" align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="92"><select name="select23" class="fulltextdmenu" onchange="GoTo(this, 'self')"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#h4">Introduction</option><option value="#h5">HA structure</option><option value="#h6">Sialic acid receptor bind...</option><option value="#h7">Antigenic variation</option><option value="#h8">Escape from infectivity-n...</option><option value="#h9">Antigenic variation in re...</option><option value="#h10">The mechanism for neutral...</option><option value="#h11">The number of antibodies ...</option><option value="#h12">Conclusions</option><option value="">Acknowledgements <<</option><option value="#h14">References</option><option value="#h1">Abbreviations: </option></select></td><td align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="10"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="32"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="16"></td><td bgcolor="#ffffff" height="16" nowrap="nowrap" width="10"></td></tr></tbody></table>This work was supported by the CNRS, the MRC and the EU program, BIOMED. We gratefully acknowledge contributions by C. Barbey, B. Barrere, T. Bizebard, A. Douglas, D. Fleury, S. Gamblin, B. Gigant, A. Hay, R. Russell, D. Stevens and D. Wiley.
<table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td class="maintextbldleft" bgcolor="#99ccff" height="16" nowrap="nowrap" width="150"> References</td><td class="maintextright" bgcolor="#99ccff" height="16" nowrap="nowrap" width="62">Go to:</td><td class="fulltextdmenu" align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="92"><select name="select23" class="fulltextdmenu" onchange="GoTo(this, 'self')"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#h4">Introduction</option><option value="#h5">HA structure</option><option value="#h6">Sialic acid receptor bind...</option><option value="#h7">Antigenic variation</option><option value="#h8">Escape from infectivity-n...</option><option value="#h9">Antigenic variation in re...</option><option value="#h10">The mechanism for neutral...</option><option value="#h11">The number of antibodies ...</option><option value="#h12">Conclusions</option><option value="#h13">Acknowledgements</option><option value="">References <<</option><option value="#h1">Abbreviations: </option></select></td><td align="right" bgcolor="#99ccff" height="16" nowrap="nowrap" valign="middle" width="10"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="32"></td><td bgcolor="#99ccff" height="16" nowrap="nowrap" width="16"></td><td bgcolor="#ffffff" height="16" nowrap="nowrap" width="10"></td></tr></tbody></table><table summary=""><tbody><tr><td align="right" valign="top" width="20"> 1 </td><td class="maintextleft">Wiley DC, Skehel JJ. The structure and function of the hemagglutinin membrane glycoprotein of influenza virus. Annu Rev Biochem 1987; 56:365?94.
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Volume 119 Page 1 - September 2006


To cite this article
Knossow, Marcel & Skehel, John J. (2006)
Variation and infectivity neutralization in influenza.
Immunology 119 (1), 1-7.
doi: 10.1111/
j.1365-2567.2006.02421.x
</td></tr></tbody></table>

[wetDirt]

Re: Immunology - Variation and infectivity neutralization in influenza

Thanks, Mingus, very interesting.


Comparing them with H1, H2 and H3 HAs from human viruses suggests that a similar mutation of Q226L, which occurred in H2 and H3 HAs, would be required for effective binding of H5 HA to α2,6-linked receptors.

So I guess here is another thing to track: Q226L. Perhaps in the Karo sequences?

[Mingus]

Re: Immunology - Variation and infectivity neutralization in influenza

Q226R have been saw in a indonesian RESRRKKR sequence.

From my amateur modelisation work I did using a universitary service offer via web in switzerland and a freeware viewer, I saw that this mutation have open a "hole" in the RBS to make it more like those from human that are larger at that place.

Q226L must do something similar and maybe even more I will check if time allow it to me one day...

That 3D modelisation capability haved recently become more and more democratised and more and more used in university and in the research world. This new easyness that no more require "giant computer" will be a new revolution in the Bio-mol world.

[Anne]

Re: Immunology - Variation and infectivity neutralization in influenza

thank for this article, mingus
so, if the RBS is larger, it's no good for us ..humm ?