Structural basis for diverse N-glycan recognition by HIV-1–neutralizing V1–V2–directed antibody PG16

Pancera, Marie; Shahzad‐ul‐Hussan, Syed; Doria‐Rose, Nicole A.; McLellan, Jason S.; Bailer, Robert T.; Dai, Keren; Loesgen, Sandra; Louder, Mark K.; Staupe, Ryan P.; Yang, Yongping; Zhang, Baoshan; Parks, Robert; Eudailey, Joshua; Lloyd, Krissey E.; Blinn, Julie; Alam, S. Munir; Haynes, Barton F.; Amin, Md. Ruhul; Wang, Lai-Xi; Burton, Dennis R.; Koff, Wayne C.; Nabel, Gary J.; Mascola, John R.; Bewley, Carole A.; Kwong, Peter D.

doi:10.1038/nsmb.2600

Cited by 266 publications

(342 citation statements)

References 61 publications

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“…A triad of aspartic acid residues provides a highly anionic potential to the tip of the PGDM1400 CDRH3 (Fig. 3C), which likely interacts with cationic residues in the gp120 V1/V2, as seen for PG9 and PG16 (29,30). The 2D-class averages of the PGDM1400 Fab-BG505 SOSIP gp140 trimer complex obtained by single-particle negative-stain electron microscopy revealed that only a single Fab is bound at the trimer apex and binds predominantly along the threefold axis, in contrast to the shallower binding angle described for PG9 (Fig.…”

Section: Somatic Variant Pgdm1400 Is Broader and More Potent Thanmentioning

confidence: 98%

A Recombinant HIV Envelope Trimer Selects for Quaternary Dependent Antibodies Targeting the Trimer Apex

SokDevin

GilsMarit

Pauthner

et al. 2014

AIDS Research and Human Retroviruses

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Broadly neutralizing antibodies (bnAbs) targeting the trimer apex of HIV envelope are favored candidates for vaccine design and immunotherapy because of their great neutralization breadth and potency. However, methods of isolating bnAbs against this site have been limited by the quaternary nature of the epitope region. Here we report the use of a recombinant HIV envelope trimer, BG505 SOSIP.664 gp140, as an affinity reagent to isolate quaternary-dependent bnAbs from the peripheral blood mononuclear cells of a chronically infected donor. The newly isolated bnAbs, named "PGDM1400-1412," show a wide range of neutralization breadth and potency. One of these variants, PGDM1400, is exceptionally broad and potent with cross-clade neutralization coverage of 83% at a median IC 50 of 0.003 μg/mL. Overall, our results highlight the utility of BG505 SOSIP.664 gp140 as a tool for the isolation of quaternary-dependent antibodies and reveal a mosaic of antibody responses against the trimer apex within a clonal family.HIV | broadly neutralizing antibodies | BG505 SOSIP | B cell | vaccine M ultiple methods have been developed to isolate HIV broadly neutralizing antibodies (bnAbs) (1-12). Hybridoma and phage display techniques were used to isolate the first generation of bnAbs including b12, 2F5, 2G12, 4E10, and Z13 (13-20). These antibodies exhibit a range of neutralization breadth against primary isolates from 30 to 90% but have moderate neutralization potency (median IC 50 of ∼2-4 μg/mL). Access to infected donors who have high serum titers of bnAbs (21,22) and the availability of newer approaches for isolating human mAbs have recently enabled the discovery of a new generation of more potent bnAbs (1-4, 6-8).One of the newer approaches involves the sorting and activation of large numbers of memory B cells using cytokine-secreting feeder cells and the subsequent high-throughput screening of supernatants for neutralization. This method led to the identification and characterization of the first of the new generation of bnAbs, PG9 and PG16 (1), and since then has revealed several sites of vulnerability to bnAb recognition on HIV envelope (Env) (1-4, 6, 7). An alternative method of bnAb isolation involves the use of soluble Env molecules or scaffold proteins as baits to select single IgG + memory B cells of interest by cell sorting (6,8,9,23,24). However, soluble baits have not been successful in isolating antibody responses targeting quaternary epitopes, including the trimer-apex site surrounding the N160 glycan, because the protein constructs used to date have not properly mimicked native Env trimers. To address this problem, GFP-labeled 293T cells that express cell-surface Env, called "GFP-293TBaL cells," were used recently to isolate antibodies 3BC176 and 3BC315 (10, 25).These antibodies do not bind soluble monomeric gp120 but do bind Env trimer, demonstrating the utility of the approach, but the method was reported to be less efficient than the use of soluble protein baits (10,25).The favorable antigenic profile of the solub...

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Section: Somatic Variant Pgdm1400 Is Broader and More Potent Thanmentioning

confidence: 98%

A Recombinant HIV Envelope Trimer Selects for Quaternary Dependent Antibodies Targeting the Trimer Apex

SokDevin

GilsMarit

Pauthner

et al. 2014

AIDS Research and Human Retroviruses

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“…Man 5 GlcNac 2 (52). V1V2 bnAb interactions with various glycans and direct strand-strand contact between the extended CDR H3 and the C strand of the V1V2 domain are common traits among individual V1V2 bnAbs (51, 52, 55, 56). For immunogen design, despite V1V2 glycan bnAb preference for binding to a quaternary epitope, PG9, PG16 and CH01 bnAbs, as well as the CH01 lineage unmutated common ancestor (UCA), can also bind a minor subset of monomeric gp120 Envs (15, 57) and minimal Env forms (58).…”

Section: Characteristics Of Broadly Neutralizing Antibodiesmentioning

confidence: 99%

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Bonsignori

Liao

Gao

et al. 2017

Immunological Reviews

164

150

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Summary Induction of HIV-1 broadly neutralizing antibodies (bnAbs) to date has only been observed in the setting of HIV-1 infection, and then only years after HIV transmission. Thus, the concept has emerged that one path to induction of bnAbs is to define the viral and immunologic events that occur during HIV-1 infection, and then to mimic those events with a vaccine formulation. This concept has led to efforts to map both virus and antibody events that occur from the time of HIV-1 transmission to development of bnAbs. This work has revealed that a virus-antibody “arms race” occurs in which a HIV-1 transmitted/founder (TF) Env induces autologous neutralizing antibodies that can not only neutralize the TF virus but also can select virus escape mutants that in turn select affinity-matured neutralizing antibodies. From these studies has come a picture of bnAb development that has led to new insights in host-pathogen interactions and, as well, led to insight into immunologic mechanisms of control of bnAb development. Here we review the progress to date in elucidating bnAb B cell lineages in HIV-1 infection, discuss new research leading to understanding the immunologic mechanisms of bnAb induction, and address issues relevant to the use of this information for the design of new HIV-1 sequential envelope vaccine candidates.

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“…2F5 and 4E10 are directed against the HIV-1 gp41 membrane-proximal external region (MPER). 53,54 IgG1b12 (b12) and VRC-CH31 are directed against the HIV-1 gp120 CD4-binding site 55,56 ; CH01, PG9, and PG16 are directed against the HIV-1 gp120 V1-V2 conformational epitope [56][57][58][59] ; and 2G12 is directed against a distinct HIV-1 gp120 epitope. 60 …”

Section: A3r5/env-imc-lucr Neutralization Assaymentioning

confidence: 99%

Optimized ReplicatingRenillaLuciferase Reporter HIV-1 Utilizing Novel Internal Ribosome Entry Site Elements for Native Nef Expression and Function

Alberti

JonesJennifer

MigliettaRiccardo

et al. 2015

AIDS Research and Human Retroviruses

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We previously developed replication-competent reporter HIV-1 (referred to herein as LucR.T2A reporter viruses), utilizing a ''ribosome skipping'' T2A peptide strategy to link Renilla luciferase (LucR) with Nef expression. The demonstrated utility for HIV-1 vaccine and transmission study applications included measurement of neutralizing antibody (NAb) activity in vaccine sera, improved cell-mediated virus inhibition assays, such as T cell-mediated virus inhibition and antibody-dependent cell-mediated cytotoxicity (ADCC) assays, and humanized mouse models. Herein, we extend our prior work and introduce reporter virus technology for applications that require fully functional Nef. We demonstrate that in CD4 +

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Structural basis for diverse N-glycan recognition by HIV-1–neutralizing V1–V2–directed antibody PG16

Cited by 266 publications

References 61 publications

A Recombinant HIV Envelope Trimer Selects for Quaternary Dependent Antibodies Targeting the Trimer Apex

A Recombinant HIV Envelope Trimer Selects for Quaternary Dependent Antibodies Targeting the Trimer Apex

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Optimized ReplicatingRenillaLuciferase Reporter HIV-1 Utilizing Novel Internal Ribosome Entry Site Elements for Native Nef Expression and Function

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