Hemagglutinin 1-Specific Immunoglobulin G and Fab Molecules Mediate Postattachment Neutralization of Influenza A Virus by Inhibition of an Early Fusion Event

Edwards, Matthew; Dimmock, Nigel J.

doi:10.1128/jvi.75.21.10208-10218.2001

Cited by 40 publications

(43 citation statements)

References 57 publications

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“…At the same time, our results rationalize the interesting findings that the entry of many viruses (27) and exocytotic fusion (28) are inhibited by macromolecules, which are added to predocked membranes and are apparently too large to rapidly enter the tight CZ.…”

Section: Discussionsupporting

confidence: 74%

Influenza Hemagglutinins Outside of the Contact Zone Are Necessary for Fusion Pore Expansion

Leikina

Mittal

Cho

et al. 2004

Journal of Biological Chemistry

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Current models for membrane fusion in diverse biological processes are focused on the local action of fusion proteins present in the contact zone where the proteins anchored in one membrane might interact directly with the other membrane. Are the fusion proteins outside of the contact zone just bystanders? Here we assess the role of these "outsider" proteins in influenza virus hemagglutinin-mediated fusion between red blood cells and either hemagglutinin-expressing cells or viral particles. To selectively inhibit or enhance the actions of hemagglutinin outsiders, the antibodies that bind to hemagglutinin and proteases that cleave it were conjugated to polystyrene microspheres too large to enter the contact zone. We also involved hemagglutinin outsiders into interactions with additional red blood cells. We find the hemagglutinin outsiders to be necessary and sufficient for fusion. Interfering with the activity of the hemagglutinin outsiders inhibited fusion. Selective conversion of hemagglutinin outsiders alone into fusioncompetent conformation was sufficient to achieve fusion. The discovered functional role of fusion proteins located outside of the contact zone suggests a tempting analogy to mechanisms by which proteins mediate membrane fission from outside of the fission site.

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Section: Discussionsupporting

confidence: 74%

Influenza Hemagglutinins Outside of the Contact Zone Are Necessary for Fusion Pore Expansion

Leikina

Mittal

Cho

et al. 2004

Journal of Biological Chemistry

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“…Homotypic bivalent antibody binding increases apparent affinity, or avidity, and thereby contributes to antibody-mediated neutralization of viruses that express high densities of surface spikes, such as respiratory syncytial and influenza viruses (50,(54)(55)(56)(57)(58). However, HIV has only a small number of surface gp160 trimers (49,50).…”

Section: Discussionmentioning

confidence: 99%

“…Because the functional properties of an antibody are strongly influenced by its binding activity, an increased affinity or avidity for a critical epitope often results in higher potency (50,(52)(53)(54)(55)(56)(57)(58); consequently, bivalent binding of specific antibodies to HIV should enhance neutralization. One directly testable prediction of this hypothesis is that anti-HIV antibodies that bind bivalently to their target show increased neutralizing potency.…”

mentioning

confidence: 99%

Enhanced HIV-1 neutralization by antibody heteroligation

Mouquet

Warncke

Scheid

et al. 2012

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

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Passive transfer of broadly neutralizing human antibodies against HIV-1 protects macaques against infection. However, HIV-1 uses several strategies to escape antibody neutralization, including mutation of the gp160 viral surface spike, a glycan shield to block antibody access to the spike, and expression of a limited number of viral surface spikes, which interferes with bivalent antibody binding. The latter is thought to decrease antibody apparent affinity or avidity, thereby interfering with neutralizing activity. To test the idea that increasing apparent affinity might enhance neutralizing activity, we engineered bispecific anti–HIV-1 antibodies (BiAbs) that can bind bivalently by virtue of one scFv arm that binds to gp120 and a second arm to the gp41 subunit of gp160. The individual arms of the BiAbs preserved the binding specificities of the original anti-HIV IgG antibodies and together bound simultaneously to gp120 and gp41. Heterotypic bivalent binding enhanced neutralization compared with the parental antibodies. We conclude that antibody recognition and viral neutralization of HIV can be improved by heteroligation.

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“…This occurs as they bind HA 1 and physically hinder the interaction with sialic acid receptors on target cells. 48 Some antibodies have been found to prevent membrane fusion; most of them recognize sites in the HA 2 region, far away from the receptor-binding site. 42,49 Quite recently, some socalled 'universal antibodies' have been generated which bind to highly conserved epitopes of the HA 2 stem region, and one of them (F16) has been shown to target part of the fusion peptide.…”

Section: Discussionmentioning

confidence: 99%

Bovine lactoferrin-derived peptides as novel broad-spectrum inhibitors of influenza virus

Ammendolia¹,

Agamennone

Pietrantoni³

et al. 2012

Pathogens and Global Health

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Bovine lactoferrin (bLf) is a multifunctional glycoprotein that plays an important role in innate immunity against infections, including influenza. Here we have dissected bLf into its C-and N-lobes and show that inhibition of influenza virus hemagglutination and cell infection is entirely attributable to the C-lobe and that all major virus subtypes, including H1N1 and H3N2, are inhibited. By far-western blotting and sequencing studies, we demonstrate that bLf C-lobe strongly binds to the HA 2 region of viral hemagglutinin, precisely the highly conserved region containing the fusion peptide. By molecular docking studies, three C-lobe fragments were identified which inhibited virus hemagglutination and infection at fentomolar concentration range. Besides contributing to explain the broad anti-influenza activity of bLf, our findings lay the foundations for exploiting bLf fragments as source of potential anti-influenza therapeutics.

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Hemagglutinin 1-Specific Immunoglobulin G and Fab Molecules Mediate Postattachment Neutralization of Influenza A Virus by Inhibition of an Early Fusion Event

Cited by 40 publications

References 57 publications

Influenza Hemagglutinins Outside of the Contact Zone Are Necessary for Fusion Pore Expansion

Influenza Hemagglutinins Outside of the Contact Zone Are Necessary for Fusion Pore Expansion

Enhanced HIV-1 neutralization by antibody heteroligation

Bovine lactoferrin-derived peptides as novel broad-spectrum inhibitors of influenza virus

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