Immunoglobulin G3 from Polyclonal Human Immunodeficiency Virus (HIV) Immune Globulin Is More Potent than Other Subclasses in Neutralizing HIV Type 1

Scharf, Orit; Golding, Hana; King, Lisa R.; Eller, Nancy; Frazier, Doug; Golding, Basil; Scott, Dorothy E.

doi:10.1128/jvi.75.14.6558-6565.2001

Cited by 94 publications

(82 citation statements)

References 46 publications

(43 reference statements)

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“…Our results are in agreement with those recently published by Yuste et al (82) which suggest that 4E10-and 2F5-like neutralizing specificities are rare in HIV-1-infected patients. Of note, 4E10 and 2F5 are both of the IgG3 subclass, which reacts poorly with protein A (39,70). However, in our three sera, IgG3 subtype antibodies are not responsible for the broad neutralizing activity, as we have demonstrated that the neutralizing specificities of interest are those reactive with protein A.…”

Section: Discussionmentioning

confidence: 78%

Dissecting the Neutralizing Antibody Specificities of Broadly Neutralizing Sera from Human Immunodeficiency Virus Type 1-Infected Donors

Dhillon

Donners

Pantophlet

et al. 2007

J Virol

176

170

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Attempts to elicit broadly neutralizing antibody responses by human immunodeficiency virus type 1 (HIV-1) vaccine antigens have been met with limited success. To better understand the requirements for crossneutralization of HIV-1, we have characterized the neutralizing antibody specificities present in the sera of three asymptomatic individuals exhibiting broad neutralization. Two individuals were infected with clade B viruses and the third with a clade A virus. The broadly neutralizing activity could be exclusively assigned to the protein A-reactive immunoglobulin G (IgG) fraction of all three donor sera. Neutralization inhibition assays performed with a panel of linear peptides corresponding to the third hypervariable (V3) loop of gp120 failed to inhibit serum neutralization of a panel of HIV-1 viruses. The sera also failed to neutralize chimeric simian immunodeficiency virus (SIV) and HIV-2 viruses displaying highly conserved gp41-neutralizing epitopes, suggesting that antibodies directed against these epitopes likely do not account for the broad neutralizing activity observed. Polyclonal IgG was fractionated on recombinant monomeric clade B gp120, and the neutralization capacities of the gp120-depleted samples were compared to that of the original polyclonal IgG. We found that the gp120-binding antibody population mediated neutralization of some isolates, but not all. Overall, the data suggest that broad neutralization results from more than one specificity in the sera but that the number of these specificities is likely small. The most likely epitope recognized by the monomeric gp120 binding neutralizing fraction is the CD4 binding site, although other epitopes, such as the glycan shield, cannot be excluded.

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Section: Discussionmentioning

confidence: 78%

Dissecting the Neutralizing Antibody Specificities of Broadly Neutralizing Sera from Human Immunodeficiency Virus Type 1-Infected Donors

Dhillon

Donners

Pantophlet

et al. 2007

J Virol

176

170

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“…Thus, an increase in Ab flexibility resulted in altered Ab/Ag interactions such that an isolate resistant to the IgG1 subclass was neutralized by the IgG3 subclass. Polyclonal serum IgG3 was found to have more neutralizing activity than IgG1 or IgG2 (47). More flexible IgG3 Abs might be capable of increased access to epitopes and efficacy than the more prevalent IgG1, and the ability of IgG3 Abs to form higher order complexes might also enhance functional effects (48 -50).…”

Section: Discussionmentioning

confidence: 99%

The Neutralization Properties of a HIV-Specific Antibody Are Markedly Altered by Glycosylation Events Outside the Antigen-Binding Domain

Miranda

Duval

Doherty

et al. 2007

The Journal of Immunology

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Neutralizing Abs constitute a pivotal mechanism of the adaptive immune response against HIV-1 infection. Yet, most of the Abs that appear in the circulation during HIV infection are nonneutralizing. In this study, we report a dramatic change of the neutralizing properties of a human Ab reactive with the nonneutralizing epitope termed cluster I on the HIV-1 transmembrane protein gp41 when the Ab was produced in Chinese hamster ovary (CHO)-K1 cells. Our laboratory has previously reported that the Ab F240, when produced in a hybridoma, is nonneutralizing as assessed by standard neutralization assays. The F240 IgG1 Ab expressed in CHO cells acquired a strong neutralization activity against a broad range of HIV isolates without a change in immunoreactivity. Sequencing of the F240 mRNAs produced in the parental hybridoma and CHO cells revealed identical sequences, suggesting that acquired neutralization resulted from cell-specific posttranslational modifications. We found that the Ab produced by CHO cells is glycosylated to a greater extent than the parental Ab produced by the hybridoma. Moreover, treatment with peptide N-glycosidase F abrogated F240 neutralization, in an isolate-specific manner, but not Ab b12 neutralization. Interestingly, the F240 isotype-switched variants IgG3 and IgG4, also expressed in CHO cells, exhibited identical immunoreactivity to IgG1 isotypes but had clear differences in viral neutralization. These results suggest that structural features of the Ig molecule other than the primary sequence of the variable regions play a more prominent role in HIV neutralization than anticipated.

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“…Most of these studies have focused on affinity differences between distinct Ig isotypes. For instance, the IgG isotype has been shown to affect the Ag-binding and HIV-neutralizing activity of monoclonal (24) and polyclonal (25) antibodies. Furthermore, 2F5 IgA2 and IgG1 display significantly different epitope specificity, antibody affinity, and functional activities (11).…”

mentioning

confidence: 99%

Thermodynamic Analysis of the Binding of 2F5 (Fab and Immunoglobulin G Forms) to Its gp41 Epitope Reveals a Strong Influence of the Immunoglobulin Fc Region on Affinity

Crespillo

Casares

Mateo

et al. 2014

Journal of Biological Chemistry

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Background:Little is known regarding the thermodynamics of binding of the broadly neutralizing anti-HIV-1 mAb 2F5 to its gp41 epitope. Results: Isothermal titration calorimetry reveals strong differences between IgG and Fab. Conclusion: Residues flanking the core epitope and the immunoglobulin Fc region contribute strongly to affinity by allosteric mechanisms. Significance: The results may help to develop new therapeutics and/or vaccines against HIV and to understanding Ag-Ab recognition.

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Immunoglobulin G3 from Polyclonal Human Immunodeficiency Virus (HIV) Immune Globulin Is More Potent than Other Subclasses in Neutralizing HIV Type 1

Cited by 94 publications

References 46 publications

Dissecting the Neutralizing Antibody Specificities of Broadly Neutralizing Sera from Human Immunodeficiency Virus Type 1-Infected Donors

Dissecting the Neutralizing Antibody Specificities of Broadly Neutralizing Sera from Human Immunodeficiency Virus Type 1-Infected Donors

The Neutralization Properties of a HIV-Specific Antibody Are Markedly Altered by Glycosylation Events Outside the Antigen-Binding Domain

Thermodynamic Analysis of the Binding of 2F5 (Fab and Immunoglobulin G Forms) to Its gp41 Epitope Reveals a Strong Influence of the Immunoglobulin Fc Region on Affinity

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