Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1
Xueling Wu,Zhi Yong Yang,Yuxing Li,Carl Magnus Hogerkorp,William R. Schief,Michael S. Seaman,Tongqing Zhou,Stephen D. Schmidt,Lan Wu,Ling Xu,Nancy S. Longo,Krisha McKee,Sijy O'Dell,Mark K. Louder,Diane Wycuff,Yu Feng,Martha Nason,Nicole A. Doria-Rose,Mark Connors,Peter D. Kwong,Mario Roederer,Richard T. Wyatt,Gary J. Nabel,John R. Mascola +23 more
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TLDR
Three broadly neutralizing antibodies are identified, isolated from an HIV-1–infected individual, that exhibited great breadth and potency of neutralization and were specific for the co-receptor CD4-binding site of the glycoprotein 120 (gp120), part of the viral Env spike.Abstract:
Cross-reactive neutralizing antibodies (NAbs) are found in the sera of many HIV-1-infected individuals, but the virologic basis of their neutralization remains poorly understood. We used knowledge of HIV-1 envelope structure to develop antigenically resurfaced glycoproteins specific for the structurally conserved site of initial CD4 receptor binding. These probes were used to identify sera with NAbs to the CD4-binding site (CD4bs) and to isolate individual B cells from such an HIV-1-infected donor. By expressing immunoglobulin genes from individual cells, we identified three monoclonal antibodies, including a pair of somatic variants that neutralized over 90% of circulating HIV-1 isolates. Exceptionally broad HIV-1 neutralization can be achieved with individual antibodies targeted to the functionally conserved CD4bs of glycoprotein 120, an important insight for future HIV-1 vaccine design.read more
Citations
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Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability
Leopold Kong,Leopold Kong,Linling He,Natalia de Val,Natalia de Val,Nemil Vora,Charles D. Morris,Parisa Azadnia,Devin Sok,Devin Sok,Bin Zhou,Dennis R. Burton,Andrew B. Ward,Andrew B. Ward,Ian A. Wilson,Jiang Zhu +15 more
TL;DR: This work computationally redesigns a largely disordered bend in heptad region 1 (HR1) of SOSIP trimers that connects the long, central HR1 helix to the fusion peptide, substantially improving the yield of soluble, well-folded trimers.
Journal ArticleDOI
Broadly neutralizing antibodies against HIV-1: Templates for a vaccine
TL;DR: The characteristics of the different classes of BrNAbs and their target epitopes, as well as factors associated with their development and implications for vaccine design are reviewed.
Journal ArticleDOI
Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers
Javier Guenaga,Viktoriya Dubrovskaya,Natalia de Val,Shailendra Kumar Sharma,Barbara Carrette,Andrew B. Ward,Richard T. Wyatt +6 more
TL;DR: Design modifications were made to increase the propensity of representatives from two of the major HIV subtypes to form highly stable trimers, allowing testing of the hypothesis that such stabilized immunogens will more efficiently elicit neutralizing antibodies in small-animal models and primates.
Journal ArticleDOI
Single-Chain Soluble BG505.SOSIP gp140 Trimers as Structural and Antigenic Mimics of Mature Closed HIV-1 Env
Ivelin S. Georgiev,M. Gordon Joyce,Yongping Yang,Mallika Sastry,Baoshan Zhang,Ulrich Baxa,Rita E. Chen,Aliaksandr Druz,Christopher R. Lees,Sandeep Narpala,Arne Schön,Joseph Van Galen,Gwo-Yu Chuang,Jason Gorman,Adam Harned,Marie Pancera,Guillaume Stewart-Jones,Cheng Cheng,Ernesto Freire,Adrian B. McDermott,John R. Mascola,Peter D. Kwong +21 more
TL;DR: Replacement of the cleavage site between gp120 and gp41 in a lead soluble gp140 construct, BG505.SOSIP, with flexible linkers can result in molecules that do not require cleavage to fold efficiently into the mature closed state, and insights into the impact of cleavage on HIV-1 Env folding are provided.
Journal ArticleDOI
Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens
George Ueda,Aleksandar Antanasijevic,Jorge A. Fallas,William Sheffler,Jeffrey Copps,Jeffrey Copps,Daniel Ellis,Geoffrey B. Hutchinson,Adam Moyer,Anila Yasmeen,Yaroslav Tsybovsky,Young-Jun Park,Matthew J. Bick,Banumathi Sankaran,Rebecca A. Gillespie,Philip J. M. Brouwer,Petrus H. Zwart,David Veesler,Masaru Kanekiyo,Barney S. Graham,Rogier W. Sanders,Rogier W. Sanders,John P. Moore,Per Johan Klasse,Andrew B. Ward,Andrew B. Ward,Neil P. King,David Baker +27 more
TL;DR: This work demonstrates that antigen-displaying protein nanoparticles can be designed from scratch, and provides a systematic way to investigate the influence of antigen presentation geometry on the immune response to vaccination.
References
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Journal ArticleDOI
Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody
Peter D. Kwong,Richard T. Wyatt,James E. Robinson,Raymond W. Sweet,Joseph Sodroski,Wayne A. Hendrickson,Wayne A. Hendrickson +6 more
TL;DR: The structure reveals a cavity-laden CD4–gp120 interface, a conserved binding site for the chemokine receptor, evidence for a conformational change upon CD4 binding, the nature of a CD4-induced antibody epitope, and specific mechanisms for immune evasion.
Journal ArticleDOI
Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection
Brandon F. Keele,Elena E. Giorgi,Elena E. Giorgi,Jesus F. Salazar-Gonzalez,Julie M. Decker,Kimmy T. Pham,Maria G. Salazar,Chuanxi Sun,Truman Grayson,Shuyi Wang,Hui Li,Xiping Wei,Chunlai Jiang,Jennifer L. Kirchherr,Feng Gao,Jeffery A. Anderson,Li Hua Ping,Ronald Swanstrom,Georgia D. Tomaras,William A. Blattner,Paul A. Goepfert,J. Michael Kilby,Michael S. Saag,Eric Delwart,Michael P. Busch,Myron S. Cohen,David C. Montefiori,Barton F. Haynes,Brian Gaschen,Gayathri Athreya,Ha Y. Lee,Natasha T. Wood,Cathal Seoighe,Alan S. Perelson,Tanmoy Bhattacharya,Tanmoy Bhattacharya,Bette T. Korber,Bette T. Korber,Beatrice H. Hahn,George M. Shaw +39 more
TL;DR: A mathematical model of random viral evolution and phylogenetic tree construction is developed and used to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection, suggesting a finite window of potential vulnerability of HIV- 1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.
Journal ArticleDOI
Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target.
Laura M. Walker,Sanjay Phogat,Po-Ying Chan-Hui,Denise Wagner,Pham Phung,Julie L. Goss,Terri Wrin,Melissa Simek,Steven P. Fling,Jennifer L. Mitcham,Jennifer Lehrman,Frances Priddy,Ole A. Olsen,Steven Frey,Phillip W. Hammond,Protocol G. Principal Investigators,Stephen M. Kaminsky,Timothy J. Zamb,Matthew Moyle,Wayne C. Koff,Pascal Poignard,Dennis R. Burton,Dennis R. Burton +22 more
TL;DR: High-throughput screening has revealed two new broadly neutralizing antibodies from a clade A–infected donor in Africa, which exhibit great potency and are able to neutralize a wide range of viruses from many different clades.
Journal ArticleDOI
Design of a Novel Globular Protein Fold with Atomic-Level Accuracy
TL;DR: A general computational strategy that iterates between sequence design and structure prediction to design a 93-residue α/β protein called Top7 with a novel sequence and topology, found experimentally to be folded and extremely stable.
Journal ArticleDOI
The antigenic structure of the HIV gp120 envelope glycoprotein
Richard T. Wyatt,Peter D. Kwong,Elizabeth Desjardins,Raymond W. Sweet,James E. Robinson,Wayne A. Hendrickson,Joseph Sodroski +6 more
TL;DR: The spatial organization of conserved neutralization epitopes on gp120 is described, using epitope maps in conjunction with the X-ray crystal structure of a ternary complex that includes a gp120 core, CD4 and a neutralizing antibody.
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