Anti-V3/Glycan and Anti-MPER Neutralizing Antibodies, but Not Anti-V2/Glycan Site Antibodies, Are Strongly Associated with Greater Anti-HIV-1 Neutralization Breadth and Potency

Jacob, Rajesh; Moyo, Thandeka; Schomaker, Michael; Abrahams, Fatima; Grau-Pujol, Berta; Dorfman, Jeffrey R.

doi:10.1128/jvi.00129-15

Cited by 29 publications

(29 citation statements)

References 65 publications

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“…Consistently, a recent study demonstrated that neutralizing antibodies to these two epitopes were associated with greater serum neutralization breadth and potency in a large patient cohort (88). However, a meaningful comparison of vaccine design strategies and epitope-specific antibody responses would require immunogens that have been optimized both structurally and antigenically.…”

Section: Discussionsupporting

confidence: 63%

Differential Antibody Responses to Conserved HIV-1 Neutralizing Epitopes in the Context of Multivalent Scaffolds and Native-Like gp140 Trimers

Morris

Azadnia

Val

et al. 2017

mBio

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Broadly neutralizing antibodies (bNAbs) have provided valuable insights into the humoral immune response to HIV-1. While rationally designed epitope scaffolds and well-folded gp140 trimers have been proposed as vaccine antigens, a comparative understanding of their antibody responses has not yet been established. In this study, we probed antibody responses to the N332 supersite and the membrane-proximal external region (MPER) in the context of heterologous protein scaffolds and native-like gp140 trimers. Ferritin nanoparticles and fragment crystallizable (Fc) regions were utilized as multivalent carriers to display scaffold antigens with grafted N332 and MPER epitopes, respectively. Trimeric scaffolds were also identified to stabilize the MPER-containing BG505 gp140.681 trimer in a native-like conformation. Following structural and antigenic evaluation, a subset of scaffold and trimer antigens was selected for immunization in BALB/c mice. Serum binding revealed distinct patterns of antibody responses to these two bNAb targets presented in different structural contexts. For example, the N332 nanoparticles elicited glycan epitope-specific antibody responses that could also recognize the native trimer, while a scaffolded BG505 gp140.681 trimer generated a stronger and more rapid antibody response to the trimer apex than its parent gp140.664 trimer. Furthermore, next-generation sequencing (NGS) of mouse splenic B cells revealed expansion of antibody lineages with long heavy-chain complementarity-determining region 3 (HCDR3) loops upon activation by MPER scaffolds, in contrast to the steady repertoires primed by N332 nanoparticles and a soluble gp140.664 trimer. These findings will facilitate the future development of a coherent vaccination strategy that combines both epitope-focused and trimer-based approaches.

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Section: Discussionsupporting

confidence: 63%

Differential Antibody Responses to Conserved HIV-1 Neutralizing Epitopes in the Context of Multivalent Scaffolds and Native-Like gp140 Trimers

Morris

Azadnia

Val

et al. 2017

mBio

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“…Given that antibodies to the oligomannose patch on HIV-1 are major contributors to neutralization breadth and potency in many HIV-infected individuals [59][60][61] , we feel that these efforts are worthwhile as part of the broader endeavor of developing an effective HIV vaccine component to elicit bnAbs.…”

Section: Discussionmentioning

confidence: 99%

Serum alpha-mannosidase as an additional barrier to eliciting oligomannose-specific HIV-1-neutralizing antibodies

Bruxelle

Kirilenko

Qureshi

et al. 2020

Preprint

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ABSTRACTOligomannose-type glycans on HIV-1 gp120 form a patch that is targeted by several broadly neutralizing antibodies (bnAbs) and that therefore is of interest to vaccine design. However, attempts to elicit similar oligomannose-specific bnAbs by immunizing with oligomannosidic glycoconjugates have only been modestly successful so far. A common assumption is that eliciting oligomannose-specific bnAbs is hindered by B cell tolerance, resulting from the presented oligomannosides being sensed as self molecules. Here, we present data, along with existing scientific evidence, supporting an additional, or perhaps alternate, explanation: serum mannosidase trimming of the presented oligomannosides in vivo. Mannosidase trimming lessens the likelihood of eliciting antibodies with capacity to bind full-sized oligomannose, which typifies the binding mode of existing bnAbs to the oligomannose patch. The rapidity of the observed trimming suggests the need for immunization strategies and/or synthetic glycosides that readily avoid or resist mannosidase trimming upon immunization and can overcome possible tolerance restrictions.

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“…The second-generation bnAb 10E8 recognizes the conserved membrane-proximal external region (MPER) of the gp41 subunit of the envelope glycoprotein (Env) (2-5), resulting in one of the highest levels of HIV-1 neutralization reported to date (1,(6)(7)(8). Antibodies against this vulnerable site also mediate the neutralization breadth and potency of sera from a subset of HIV-1-infected individuals (8,9). Despite reported similarities in the epitope binding profile with the first-generation anti-MPER bnAb 4E10, 10E8 displays high neutralization potency and very limited, if any, polyreactivity in comparison (8, 10).…”

mentioning

confidence: 99%

Functional Optimization of Broadly Neutralizing HIV-1 Antibody 10E8 by Promotion of Membrane Interactions

Rujas

Leaman

Insausti

et al. 2018

J Virol

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The 10E8 antibody targets a helical epitope in the membrane-proximal external region (MPER) and transmembrane domain (TMD) of the envelope glycoprotein (Env) subunit gp41 and is among the broadest known neutralizing antibodies against HIV-1. Accordingly, this antibody and its mechanism of action valuably inform the design of effective vaccines and immunotherapies. 10E8 exhibits unusual adaptations to attain specific, high-affinity binding to the MPER at the viral membrane interface. Reversing the charge of the basic paratope surface (from net positive to net negative) reportedly lowered its neutralization potency. Here, we hypothesized that by increasing the net positive charge in similar polar surface patches, the neutralization potency of the antibody may be enhanced. We found that an increased positive charge at this paratope surface strengthened an electrostatic interaction between the antibody and lipid bilayers, enabling 10E8 to interact spontaneously with membranes. Notably, the modified 10E8 antibody did not gain any apparent polyreactivity and neutralized virus with a significantly greater potency. Binding analyses indicated that the optimized 10E8 antibody bound with a higher affinity to the epitope peptide anchored in lipid bilayers and to Env spikes on virions. Overall, our data provide a proof of principle for the rational optimization of 10E8 via manipulation of its interaction with the membrane element of its epitope. However, the observation that a similar mutation strategy did not affect the potency of the first-generation anti-MPER antibody 4E10 shows possible limitations of this principle. Altogether, our results emphasize the crucial role played by the viral membrane in the antigenicity of the MPER-TMD of HIV-1. The broadly neutralizing antibody 10E8 blocks infection by nearly all HIV-1 isolates, a capacity which vaccine design seeks to reproduce. Engineered versions of this antibody also represent a promising treatment for HIV infection by passive immunization. Understanding its mechanism of action is therefore important to help in developing effective vaccines and biologics to combat HIV/AIDS. 10E8 engages its helical MPER epitope where the base of the envelope spike submerges into the viral membrane. To enable this interaction, this antibody evolved an unusual property: the ability to interact with the membrane surface. Here, we provide evidence that 10E8 can be made more effective by enhancing its interactions with membranes. Our findings strengthen the idea that to elicit antibodies similar to 10E8, vaccines must reproduce the membrane environment where these antibodies perform their function.

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Anti-V3/Glycan and Anti-MPER Neutralizing Antibodies, but Not Anti-V2/Glycan Site Antibodies, Are Strongly Associated with Greater Anti-HIV-1 Neutralization Breadth and Potency

Cited by 29 publications

References 65 publications

Differential Antibody Responses to Conserved HIV-1 Neutralizing Epitopes in the Context of Multivalent Scaffolds and Native-Like gp140 Trimers

Differential Antibody Responses to Conserved HIV-1 Neutralizing Epitopes in the Context of Multivalent Scaffolds and Native-Like gp140 Trimers

Serum alpha-mannosidase as an additional barrier to eliciting oligomannose-specific HIV-1-neutralizing antibodies

Functional Optimization of Broadly Neutralizing HIV-1 Antibody 10E8 by Promotion of Membrane Interactions

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