Reassessment of autoreactivity of the broadly neutralizing HIV antibodies 4E10 and 2F5 and retrospective analysis of clinical safety data

Vcelar, Brigitta; Stiegler, Gabriela; Wolf, Hermann M.; Muntean, W.; Leschnik, B.; Mehandru, Saurabh; Markowitz, Martin; Armbruster, Christine; Kunert, Renate; Eibl, Martha M.; Katinger, Hermann

doi:10.1097/qad.0b013e328285da15

Cited by 46 publications

(54 citation statements)

References 33 publications

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“…Explicitly, the hypothesis is that the MPER antigenically mimics cardiolipin, an autoantigen; therefore, MPER immunogens fail to induce neutralizing anti-MPER antibodies because B cells with autoreactive antibody specificities are negatively regulated by tolerance mechanisms. However, we and others have found that 2F5 does not bind to CL in diagnostic assays of antiphospholipid syndrome or to liposome surfaces (21,25,28), which suggests that difficulties in eliciting neutralizing antibodies against MPER immunogens is not generally related to CL reactivity. Furthermore, it has been shown that antibody responses can be elicited to MPER immunogens, only that these antibodies are not potently neutralizing (44), suggesting again that tolerance is not the issue, but some qualitative difference between neutralizing and "nonneutralizing" MPER antibodies.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it has become increasingly clear that 4E10 binds to lipids in the absence of the MPER (21,(23)(24)(25)(26)(27)(28)(29). These studies have generated models of 4E10 epitope recognition (21,23), but they have not yet fully addressed which antibody region(s) bind lipid and, of particular importance for vaccine design, whether lipid interaction is an essential component of MPER-mediated neutralization.…”

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confidence: 99%

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Aromatic residues at the edge of the antibody combining site facilitate viral glycoprotein recognition through membrane interactions

Scherer

Leaman

Zwick

et al. 2010

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

107

118

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The broadly neutralizing anti-HIV antibody 4E10 recognizes an epitope very close to the virus membrane on the glycoprotein gp41. It was previously shown that epitope recognition improves in a membrane context and that 4E10 binds directly, albeit weakly, to lipids. Furthermore, a crystal structure of Fab 4E10 complexed to an epitope peptide revealed that the centrally placed, protruding H3 loop of the antibody heavy chain does not form peptide contacts. To investigate the hypothesis that the H3 loop apex might interact with the viral membrane, two Trp residues in this region were substituted separately or in combination with either Ala or Asp by site-directed mutagenesis. The resultant IgG variants exhibited similar affinities for an epitope peptide as WT 4E10 but lower apparent affinities for both viral membrane mimetic liposomes and Env(−) virus. Variants also exhibited lower apparent affinities for Env(+) virions and failed to significantly neutralize a number of 4E10-sensitive viruses. For the extremely sensitive HXB2 virus, variants did neutralize, but at 37-to >250-fold lower titers than WT 4E10, with Asp substitutions exerting a greater effect on neutralization potency than Ala substitutions. Because reductions in lipid binding reflect trends in neutralization potency, we conclude that Trp residues in the antibody H3 loop enable membrane proximal epitope recognition through favorable lipid interactions. The requirement for lipophilic residues such as Trp adjacent to the antigen binding site may explain difficulties in eliciting 4E10-like neutralizing antibody responses by immunization and helps define a unique motif for antibody recognition of membrane proximal antigens.4E10 | gp41 | HIV | neutralizing antibody | tryptophan

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Aromatic residues at the edge of the antibody combining site facilitate viral glycoprotein recognition through membrane interactions

Scherer

Leaman

Zwick

et al. 2010

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

107

118

View full text Add to dashboard Cite

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“…The latter finding has led to the suggestion that 2F5 might be autoreactive (12), although passive transfusion of 2F5 does not appear to have deleterious effects (38) and 2F5 failed to react in some clinically based assays for autoreactive lipid antibodies (31,39). The crystal structures of the 2F5 antibody in complex with its gp41 MPER epitope revealed that, despite the 22-residue length of the 2F5 heavy chain third complementarity-determining region (CDR H3) loop, contacts with the gp41 MPER peptide are made predominantly at the loop base.…”

mentioning

confidence: 99%

Relationship between Antibody 2F5 Neutralization of HIV-1 and Hydrophobicity of Its Heavy Chain Third Complementarity-Determining Region

Ofek

McKee

Yang

et al. 2010

J Virol

109

118

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The membrane-proximal external region (MPER) of the HIV-1 gp41 transmembrane glycoprotein is the target of the broadly neutralizing antibody 2F5. Prior studies have suggested a two-component mechanism for 2F5-mediated neutralization involving both structure-specific recognition of a gp41 protein epitope and nonspecific interaction with the viral lipid membrane. Here, we mutationally alter a hydrophobic patch on the third complementarity-determining region of the heavy chain (CDR H3) of the 2F5 antibody and assess the abilities of altered 2F5 variants to bind gp41 and to neutralize diverse strains of HIV-1. CDR H3 alterations had little effect on the affinity of 2F5 variants for a peptide corresponding to its gp41 epitope. In contrast, strong effects and a high degree of correlation (P < 0.0001) were found between virus neutralization and CDR H3 hydrophobicity, as defined by predicted free energies of transfer from water to a lipid bilayer interface or to octanol. The effect of CDR H3 hydrophobicity on neutralization was independent of isolate sensitivity to 2F5, and CDR H3 variants with tryptophan substitutions were able to neutralize HIV-1 ϳ10-fold more potently than unmodified 2F5. A threshold was observed for increased hydrophobicity of the 2F5 CDR H3 loop beyond which effects on 2F5-mediated neutralization leveled off. Together, the results provide a more complete understanding of the 2F5 mechanism of HIV-1 neutralization and indicate ways to enhance the potency of MPER-directed antibodies.

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“…4E10, in particular, has affinity for lipids in addition to its peptide binding capacity (2,4,32,66,69,75,77). The affinity of 2F5 for lipids is controversial (38,46,66,70,77,85).…”

mentioning

confidence: 99%

Binding of Anti-Membrane-Proximal gp41 Monoclonal Antibodies to CD4-Liganded and -Unliganded Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus Virions

Rathinakumar

Dutta

Zhu

et al. 2012

J Virol

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Reassessment of autoreactivity of the broadly neutralizing HIV antibodies 4E10 and 2F5 and retrospective analysis of clinical safety data

Cited by 46 publications

References 33 publications

Aromatic residues at the edge of the antibody combining site facilitate viral glycoprotein recognition through membrane interactions

Aromatic residues at the edge of the antibody combining site facilitate viral glycoprotein recognition through membrane interactions

Relationship between Antibody 2F5 Neutralization of HIV-1 and Hydrophobicity of Its Heavy Chain Third Complementarity-Determining Region

Binding of Anti-Membrane-Proximal gp41 Monoclonal Antibodies to CD4-Liganded and -Unliganded Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus Virions

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