A H1 hemagglutinin of a human influenza A virus with a carbohydrate-modulated receptor binding site and an unusual cleavage site

Günther, Isolde; Glatthaar, B.; Döller, G; Garten, Wolfgang

doi:10.1016/0168-1702(93)90078-2

Cited by 36 publications

(17 citation statements)

References 45 publications

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“…The HA of LPAI viruses is activated at the monobasic cleavage site, that is usually an arginine but sometimes a lysine [94,95], by proteases that are present only in respiratory or intestinal epithelial tissues. Infection is therefore restricted to these organs.…”

Section: H D Klenk Et Almentioning

confidence: 99%

Molecular mechanisms of interspecies transmission and pathogenicity of influenza viruses: Lessons from the 2009 pandemic

2011

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The emergence of the 2009 H1N1 virus pandemic was unexpected, since it had been predicted that the next pandemic would be caused by subtype H5N1. We also had to learn that a pandemic does not necessarily require the introduction of a new virus subtype into the human population, but that it may result from antigenic shift within the same subtype. The new variant was derived from human and animal viruses by genetic reassortment in the pig, supporting the concept that this animal is the mixing vessel for the generation of new human influenza viruses. Although it is generally believed that the 2009 outbreak was mild, there have been severe cases particularly among the young and the middle-aged. Pathogenicity and host range are determined to a large extent by the polymerase, the haemagglutinin and the NS1 protein of influenza A viruses. There is evidence that mutations of these proteins may change the pathogenicity of the new virus.

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Section: H D Klenk Et Almentioning

confidence: 99%

Molecular mechanisms of interspecies transmission and pathogenicity of influenza viruses: Lessons from the 2009 pandemic

2011

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“…Glycans near antigenic peptide epitopes interfere with antibody recognition (12), and glycans near the proteolytic activation site of HA modulate cleavage and influence the infectivity of influenza virus (13). Mutational deletion of HA glycosylation sites can affect viral receptor binding (14). Our analysis of HA sequences revealed that the peptide sequences around the glycosylation sites are highly conserved (Fig.…”

mentioning

confidence: 95%

Glycans on influenza hemagglutinin affect receptor binding and immune response

Wang

Chen

Tseng

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

280

256

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Recent cases of avian influenza H5N1 and the swine-origin 2009 H1N1 have caused a great concern that a global disaster like the 1918 influenza pandemic may occur again. Viral transmission begins with a critical interaction between hemagglutinin (HA) glycoprotein, which is on the viral coat of influenza, and sialic acid (SA) containing glycans, which are on the host cell surface. To elucidate the role of HA glycosylation in this important interaction, various defined HA glycoforms were prepared, and their binding affinity and specificity were studied by using a synthetic SA microarray. Truncation of the N-glycan structures on HA increased SA binding affinities while decreasing specificity toward disparate SA ligands. The contribution of each monosaccharide and sulfate group within SA ligand structures to HA binding energy was quantitatively dissected. It was found that the sulfate group adds nearly 100-fold (2.04 kcal/mol) in binding energy to fully glycosylated HA, and so does the biantennary glycan to the monoglycosylated HA glycoform. Antibodies raised against HA protein bearing only a single N-linked GlcNAc at each glycosylation site showed better binding affinity and neutralization activity against influenza subtypes than the fully glycosylated HAs elicited. Thus, removal of structurally nonessential glycans on viral surface glycoproteins may be a very effective and general approach for vaccine design against influenza and other human viruses.flu vaccine ͉ glycan binding ͉ glycosylation T he highly pathogenic H5N1 and the 2009 swine-origin influenza A (H1N1) viruses have caused global outbreaks and raised a great concern that further changes in the viruses may occur to bring about a deadly pandemic (1, 2). Important contributions to our understanding of influenza infections have come from the studies on hemagglutinin (HA), a viral coat glycoprotein that binds to specific sialylated glycan receptors in the respiratory tract, allowing the virus to enter the cell (3-6). To cross the species barrier and infect the human population, avian HA must change its receptorbinding preference from a terminally sialylated glycan that contains ␣2,3 (avian)-linked to ␣2,6 (human)-linked sialic acid motifs (7), and this switch could occur through only two mutations, as in the 1918 pandemic (8). Understanding the factors that affect influenza binding to glycan receptors is thus critical for developing methods to control any future crossover influenza strains that have pandemic potential.HA is a homotrimeric transmembrane protein with an ectodomain composed of a globular head and a stem region (3). Both regions carry N-linked oligosaccharides (9), which affect the functional properties of HA (10, 11). Among different subtypes of influenza A viruses, there is extensive variation in the glycosylation sites of the head region, whereas the stem oligosaccharides are more conserved and required for fusion activity (11). Glycans near antigenic peptide epitopes interfere with antibody recognition (12), and glycans near the proteolytic ...

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“…Amino acid sequence comparisons between naturally occurring avirulent and virulent avian influenza viruses have shown that HAs with restricted cleavability (avirulent type) usually have a single arginine (R) whereas those with high cleavability (virulent type) have multiple basic residues situated immediately upstream of the cleavage site (17) ( Table 3). The majority of influenza A viruses have R at the carboxyl terminus of HA1 and glycine (G) at the amino terminus of HA2, although some have lysine (K) at the former position (63,93). Among H5 viruses, proline (P) and glutamine (Q), located proximally upstream of the HA1 carboxyl terminus, are also conserved.…”

Section: Sequence Requirement For High Hemagglutinin Cleavability Andmentioning

confidence: 99%

Pandemic Threat Posed by Avian Influenza A Viruses

2001

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Influenza pandemics, defined as global outbreaks of the disease due to viruses with new antigenic subtypes, have exacted high death tolls from human populations. The last two pandemics were caused by hybrid viruses, or reassortants, that harbored a combination of avian and human viral genes. Avian influenza viruses are therefore key contributors to the emergence of human influenza pandemics. In 1997, an H5N1 influenza virus was directly transmitted from birds in live poultry markets in Hong Kong to humans. Eighteen people were infected in this outbreak, six of whom died. This avian virus exhibited high virulence in both avian and mammalian species, causing systemic infection in both chickens and mice. Subsequently, another avian virus with the H9N2 subtype was directly transmitted from birds to humans in Hong Kong. Interestingly, the genes encoding the internal proteins of the H9N2 virus are genetically highly related to those of the H5N1 virus, suggesting a unique property of these gene products. The identification of avian viruses in humans underscores the potential of these and similar strains to produce devastating influenza outbreaks in major population centers. Although highly pathogenic avian influenza viruses had been identified before the 1997 outbreak in Hong Kong, their devastating effects had been confined to poultry. With the Hong Kong outbreak, it became clear that the virulence potential of these viruses extended to humans

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A H1 hemagglutinin of a human influenza A virus with a carbohydrate-modulated receptor binding site and an unusual cleavage site

Cited by 36 publications

References 45 publications

Molecular mechanisms of interspecies transmission and pathogenicity of influenza viruses: Lessons from the 2009 pandemic

Molecular mechanisms of interspecies transmission and pathogenicity of influenza viruses: Lessons from the 2009 pandemic

Glycans on influenza hemagglutinin affect receptor binding and immune response

Pandemic Threat Posed by Avian Influenza A Viruses

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