Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo

Medina-Ramírez, Max; Garcés, Fernando; Escolano, Amelia; Skog, Patrick; Taeye, Steven W. de; Moral-Sánchez, Iván del; McGuire, Andrew T.; Yasmeen, Anila; Behrens, Anna‐Janina; Ozorowski, Gabriel; Kerkhof, Tom L.G.M. van den; Freund, Natalia T.; Dosenovic, Pia; Hua, Yuanzi; Gitlin, Alexander D.; Cupo, Albert; Woude, Patricia van der; Golabek, Michael; Sliepen, Kwinten; Blane, Tanya R.; Kootstra, Neeltje A.; Breemen, Mariëlle J. van; Pritchard, Laura K.; Stanfield, Robyn L.; Crispin, Max; Ward, Andrew B.; Stamatatos, Leonidas; Klasse, Per Johan; Moore, John P.; Nemazee, David; Nussenzweig, Michel C.; Wilson, Ian A.; Sanders, Rogier W.

doi:10.1084/jem.20161160

Cited by 156 publications

(232 citation statements)

References 93 publications

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“…Their value is that they serve as a template for structure-guided design efforts that are intended to increase the affinity of Env binding; and as a device to measure the outcome of the engineering efforts. Most of the work in this area to date has been carried out using constructs based on gp120 monomers such as the engineered outer domain (eOD) or the 426c gp120-core families of proteins (193–195 197–199). The design of these constructs generally involves deleting variable loops and/or glycan sites to increase the accessibility of the CD4bs, which is consistent with their targeted focus on the CD4bs family of bNAbs (193–195 197–199).…”

Section: Lineage Vaccines Based On Native-like Trimersmentioning

confidence: 99%

“…Accordingly, our group used structural and other insights to engineer germline-targeting (GT) SOSIP trimers so that they would engage multiple gl-bNAbs in vitro and, by extension, in vivo (200). The most advanced of the new trimers is BG505 SOSIP.v4.1-GT1, which was based on the stabilized SOSIP.v4.1 construct described above (123).…”

Section: Lineage Vaccines Based On Native-like Trimersmentioning

confidence: 99%

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Native‐like Env trimers as a platform for HIV‐1 vaccine design

Sanders

Moore

2017

Immunological Reviews

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Summary We describe the development and potential use of various designs of recombinant HIV-1 envelope glycoprotein trimers that mimic the structure of the virion-associated spike, which is the target for neutralizing antibodies. The goal of trimer development programs is to induce broadly neutralizing antibodies with the potential to intervene against multiple circulating HIV-1 strains. Among topics we address are the designs of various constructs; how native-like trimers can be produced and purified; the properties of such trimers in vitro and their immunogenicity in various animals; and the immunization strategies that may lead to the eventual elicitation of broadly neutralizing antibodies. In summary, native-like trimers are a now a platform for structure- and immunology-based design improvements that could eventually yield immunogens of practical value for solving the long-standing HIV-1 vaccine problem.

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Section: Lineage Vaccines Based On Native-like Trimersmentioning

confidence: 99%

Section: Lineage Vaccines Based On Native-like Trimersmentioning

confidence: 99%

Native‐like Env trimers as a platform for HIV‐1 vaccine design

Sanders

Moore

2017

Immunological Reviews

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223

260

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“…In addition to eOD-GT8, other germline-targeting immunogens are being developed, including a core gp120 derived from a clade C Env, 426c, which binds VRC01-class germline precursors and primes germline receptor-expressing B cells in vivo [30,34], and modified versions of the BG505 SOSIP.664 trimer, which can bind multiple bnAb germline specificities [35] (Figure 1B). Overall, these strategies aim to activate VRC01-like precursor B cell receptors (BCRs) with a germline-targeting immunogen, followed by boosting with more native-like Env molecules to shepherd Ab responses along favorable bnAb developmental pathways [29–33].…”

Section: Approaches To Design Immunogens Capable Of Inducing Hiv Bnabsmentioning

confidence: 99%

“…The use of naturally existing or artificially created glycan holes on Env trimer immunogens to increase accessibility of immunoquiescent epitopes or to improve germline Ab binding has also been extended to the CD4bs bnAb epitope [35,40,41]. However, the glycan shield protects the underlying protein from immune recognition, therefore these immunogens may also increase accessibility of immunodominant, non-bnAb epitopes.…”

Section: Approaches To Design Immunogens Capable Of Inducing Hiv Bnabsmentioning

confidence: 99%

Strategies for a multi-stage neutralizing antibody-based HIV vaccine

Andrabi

Bhiman

Burton

2018

Current Opinion in Immunology

102

100

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A critical property of a prophylactic HIV vaccine is likely to be its ability to elicit broadly neutralizing antibodies (bnAbs). BnAbs typically have multiple unusual features and are generated in a fraction of HIV-infected individuals through complex pathways. Current vaccine design approaches seek to trigger quite rare B cell precursors and then steer affinity maturation toward bnAbs in a multi-stage multi-component immunization approach. These vaccine design strategies have been facilitated by molecular descriptions of bnAb interactions with stabilized HIV trimers, the use of an array of sophisticated approaches for immunogen design, the development of novel animal models for immunogen evaluation and advanced technologies to interrogate Ab responses. In this review, we will discuss leading HIV bnAb vaccine immunogens, immunization strategies and future improvements.

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“…For example, many patients that develop bNAbs have circulating virus missing key glycans. It has been hypothesized that the induction of bNAbs could be achieved by the use of immunogens primers that help expand B-cell linages corresponding to the desired bNAbs [82–86]. Glycosylation analytics have shown that deletion of multiple glycans has minimal effect of neighboring glycans and potentially multiple holes can be incorporated into a single immunogen without adversely affecting the remaining glycan-dependent epitopes [79].…”

Section: Expert Commentarymentioning

confidence: 99%

Glycosylation profiling to evaluate glycoprotein immunogens against HIV-1

Behrens

Struwe

Crispin

2017

Expert Review of Proteomics

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Introduction Much of the efforts to develop a vaccine against the human immunodeficiency virus (HIV) have focused on the design of recombinant mimics of the viral attachment glycoprotein (Env). The leading immunogens exhibit native-like antigenic properties and are being investigated for their ability to induce broadly neutralizing antibodies (bNAbs). Understanding the relative abundance of glycans at particular glycosylation sites on these immunogens is important as most bNAbs have evolved to recognize or evade the dense coat of glycans that masks much of the protein surface. Understanding the glycan structures on candidate immunogens enables triaging between native-like conformations and immunogens lacking key structural features as steric constraints limit glycan processing. The sensitivity of the processing state of a particular glycan to its structural environment has led to the need for quantitative glycan profiling and site-specific analysis to probe the structural integrity of immunogens. Areas covered We review analytical methodologies for HIV immunogen evaluation and discuss how these studies have led to a greater understanding of the structural constraints that control the glycosylation state of the HIV attachment and fusion spike. Expert commentary Total composition and site-specific glycosylation profiling are emerging as standard methods in the evaluation of Env-based immunogen candidates.

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Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo

Cited by 156 publications

References 93 publications

Native‐like Env trimers as a platform for HIV‐1 vaccine design

Native‐like Env trimers as a platform for HIV‐1 vaccine design

Strategies for a multi-stage neutralizing antibody-based HIV vaccine

Glycosylation profiling to evaluate glycoprotein immunogens against HIV-1

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