Oligomer-Specific Conformations of the Human Immunodeficiency Virus (HIV-1) gp41 Envelope Glycoprotein Ectodomain Recognized by Human Monoclonal Antibodies

Yuan, Wen; Xing, Li; Kasterka, Marta; Gorny, Miroslaw K.; Zolla‐Pazner, Susan; Sodroski, Joseph

doi:10.1089/aid.2008.0213

Cited by 25 publications

(37 citation statements)

References 49 publications

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“…Of the three cluster II MAbs, 98-6 is distinct in that it bound to linear MPER peptides and gp140 oligomers. These results are consistent with previous reports that 98-6 is reactive with both the free HR-2 peptide and the complexed HR-1/ HR-2 peptides (21) and is reactive with dimeric and trimeric forms of gp140 (56). The lack of reactivity of MAb 98-6 with MPER peptide complexes suggest that it may fail to recognize the constrained conformation on the membrane surface since the epitope of this MAb is located N-terminal to the 2F5 core (56) and such residues are more likely to be solvent exposed (11,46).…”

Section: Discussionsupporting

confidence: 93%

“…These results are consistent with previous reports that 98-6 is reactive with both the free HR-2 peptide and the complexed HR-1/ HR-2 peptides (21) and is reactive with dimeric and trimeric forms of gp140 (56). The lack of reactivity of MAb 98-6 with MPER peptide complexes suggest that it may fail to recognize the constrained conformation on the membrane surface since the epitope of this MAb is located N-terminal to the 2F5 core (56) and such residues are more likely to be solvent exposed (11,46). Exposure of the 98-6 epitope on infected cells was enhanced following soluble CD4 treatment, which suggests that the conformational changes induced upon CD4 binding result in the exposure of gp41 epitopes that include the 98-6 binding site (40,47).…”

Section: Discussionsupporting

confidence: 93%

“…Both 126-6 and 167-D react with complexed HR-1 and HR-2 peptides (the gp41 N51-C43 peptide complex) but not with either alone (21,56). This is consistent with our results that both MAbs bound strongly to gp140 oligomers and showed no reactivity with MPER peptide-lipid conjugates.…”

Section: Discussionsupporting

confidence: 91%

“…This is consistent with our results that both MAbs bound strongly to gp140 oligomers and showed no reactivity with MPER peptide-lipid conjugates. The epitope for MAb 126-6 has been mapped to a region N-terminal to gp41 aa 648, and its requirement for a gp140 trimer-specific conformation suggests that the MAb likely targets the postfusion state of gp41 (56). Of the three cluster II MAbs, 98-6 is distinct in that it bound to linear MPER peptides and gp140 oligomers.…”

Section: Discussionmentioning

confidence: 99%

“…The broadly neutralizing MAbs 2F5 and 4E10 recognize epitopes that are within the gp41 membrane-proximal external region (MPER), with the 2F5 epitope being adjacent to the cluster II region and that of 4E10 mapping outside the cluster II and being more membrane proximal (cluster III). There is some overlap between cluster II epitopes and the epitope recognized by MPER MAb 2F5 (56). Thus, cluster II human MAbs (98-6, 126-6, and 167-D) can partially cross-block 2F5 MAb binding to HIV-1 Env gp140 oligomers (3).…”

mentioning

confidence: 99%

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Nonneutralizing HIV-1 gp41 Envelope Cluster II Human Monoclonal Antibodies Show Polyreactivity for Binding to Phospholipids and Protein Autoantigens

Dennison

Anasti

Scearce

et al. 2011

J Virol

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HIV-1 gp41 envelope antibodies, which are frequently induced in HIV-1-infected individuals, are predominantly nonneutralizing. The rare and difficult-to-induce neutralizing antibodies (2F5 and 4E10) that target gp41 membrane-proximal epitopes (MPER) are polyspecific and require lipid binding for HIV-1 neutralization. These results raise the questions of how prevalent polyreactivity is among gp41 antibodies and how the binding properties of gp41-nonneutralizing antibodies differ from those of antibodies that are broadly neutralizing. In this study, we have characterized a panel of human gp41 antibodies with binding specificities within the immunodominant cluster I (gp41 amino acids [aa] 579 to 613) or cluster II (gp41 aa 644 to 667) for reactivity to autoantigens, to the gp140 protein, and with MPER peptide-lipid conjugates. We report that while none of the gp41 cluster I antibodies studied were polyspecific, all three gp41 cluster II antibodies bound either to lipids or autoantigens, thus showing the propensity of cluster II antibodies to manifest polyreactivity. All cluster II gp41 monoclonal antibodies (MAbs), including those that were lipid reactive, failed to bind to gp41 MPER peptide-lipid complexes. Cluster II antibodies bound strongly with nanomolar binding affinity (dissociation constant [K d ]) to oligomeric gp140 proteins, and thus, they recognize conformational epitopes on gp41 that are distinct from those of neutralizing gp41 antibodies. These results demonstrate that lipid-reactive gp41 cluster II antibodies are nonneutralizing due to their inability to bind to the relevant neutralizing epitopes on gp41.Anti-HIV-1 gp41 envelope (Env) antibodies (Abs) are frequently induced in HIV-1-infected individuals (6,8,58). The antigenic determinants of gp41 have been mapped with a large panel of human gp41 antibodies (21,32,55,61). Whereas cluster I monoclonal Abs (MAbs) are directed against the immunodominant region (gp41 amino acids [aa] 579 to 613) of the gp41 envelope, a subset of human HIV-1 MAbs specific for "cluster II" (55) show binding specificities for the gp41 region, which includes HR-2 (heptad repeat 2) (aa 644 to 667) (21, 35, 55). The broadly neutralizing MAbs 2F5 and 4E10 recognize epitopes that are within the gp41 membrane-proximal external region (MPER), with the 2F5 epitope being adjacent to the cluster II region and that of 4E10 mapping outside the cluster II and being more membrane proximal (cluster III). There is some overlap between cluster II epitopes and the epitope recognized by MPER MAb 2F5 (56). Thus, cluster II human can partially cross-block 2F5 MAb binding to HIV-1 Env gp140 oligomers (3).Anti-gp41 antibodies whose epitopes are within the gp41 HR-2 region are largely nonneutralizing, with only rare neutralizing MAbs (9,36,45,61). One each of cluster I (clone 3) and cluster II (98-6) MAbs have been reported to weakly neutralize select HIV-1 strains (19,25). Both cluster I and cluster II MAbs, however, can bind HIV-1-infected cells and HIV-1 virions and also have been reported to ...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Nonneutralizing HIV-1 gp41 Envelope Cluster II Human Monoclonal Antibodies Show Polyreactivity for Binding to Phospholipids and Protein Autoantigens

Dennison

Anasti

Scearce

et al. 2011

J Virol

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Trimerization of the HIV Transmembrane Domain in Lipid Bilayers Modulates Broadly Neutralizing Antibody Binding

et al. 2016

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The membrane-proximal external region (MPER) of HIV gp41 is an established target of antibodies that neutralize a broad range of HIV isolates. To evaluate the role of the transmembrane (TM) domain, synthetic MPER-derived peptides were incorporated into lipid nanoparticles using natural and designed TM domains, and antibody affinity was measured using immobilized and solution-based techniques. Peptides incorporating the native HIV TM domain exhibit significantly stronger interactions with neutralizing antibodies than peptides with a monomeric TM domain. Furthermore, a peptide with a trimeric, three-helix bundle TM domain recapitulates the binding profile of the native sequence. These studies suggest that neutralizing antibodies can bind the MPER when the TM domain is a three-helix bundle and this presentation could influence the binding of neutralizing antibodies to the virus. Lipid-bilayer presentation of viral antigens in Nanodiscs is a new platform for evaluating neutralizing antibodies. KeywordsPeptides; Membrane Proteins; Nanostructures; Antibodies; HIV The membrane proximal external region (MPER) is a portion of the envelope glycoprotein gp41 on the surface of HIV virions. The MPER is critical to membrane fusion and infection, and is one of the most highly conserved regions of HIV [2] . A number of broadly neutralizing antibodies including 4E10, Z13e1, 2F5, and 10E8 have been identified that target overlapping regions of the MPER, and a broad analysis of patient sera suggest that MPER-directed antibodies are more common than previously thought [3] . Neutralizing antibodies identified from HIV+ individuals have been shown to provide protection against Correspondence to: Philip E. Dawson. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript intravenous and mucosal challenge in passive transfer animal studies, suggesting that a neutralizing antibody response could protect against HIV [4] . Despite the apparent linear nature of described MPER epitopes, the design of effective MPER immunogens has had limited success [5] . Thus the MPER is ripe for a reverse vaccinology approach to elucidate the interactions between known broadly neutralizing antibodies and their epitopes in order to direct the iterative design of immunogens.The structure of the MPER is largely unknown in the context of Env trimers, despite highresolution structural information regarding Env trimers both on the virion surface and in soluble forms. Cryo-EM data of virion surfaces show low density and low signal to noise at the MPER, suggesting less protein mass or greater disorder in this region [6] . Recent cryo-EM [1] and x-ray crystallography structures [7] of stabilized soluble gp41-gp120 trimers required removal of the MPER to obtain stable constructs. The conformation of the MPER is still an open question of great interest and import to antigen design and general understanding of HIV.Recognizing the importance of the membrane in understanding the MPER, the MPER has been presented in association ...

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Trimerization of the HIV Transmembrane Domain in Lipid Bilayers Modulates Broadly Neutralizing Antibody Binding

et al. 2016

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Oligomer-Specific Conformations of the Human Immunodeficiency Virus (HIV-1) gp41 Envelope Glycoprotein Ectodomain Recognized by Human Monoclonal Antibodies

Cited by 25 publications

References 49 publications

Nonneutralizing HIV-1 gp41 Envelope Cluster II Human Monoclonal Antibodies Show Polyreactivity for Binding to Phospholipids and Protein Autoantigens

Nonneutralizing HIV-1 gp41 Envelope Cluster II Human Monoclonal Antibodies Show Polyreactivity for Binding to Phospholipids and Protein Autoantigens

Trimerization of the HIV Transmembrane Domain in Lipid Bilayers Modulates Broadly Neutralizing Antibody Binding

Trimerization of the HIV Transmembrane Domain in Lipid Bilayers Modulates Broadly Neutralizing Antibody Binding

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