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
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The N276 glycosylation site is required for HIV-1 neutralization by the CD4 binding site specific HJ16 monoclonal antibody.
Sunita S. Balla-Jhagjhoorsingh,Davide Corti,Leo Heyndrickx,Elisabeth Willems,Katleen Vereecken,David Davis,Guido Vanham +6 more
TL;DR: Data indicate that binding of the CD4bs specific HJ 16 mAb critically depends on the interaction with the N276-glycan, thus indicating that HJ16 is the first glycan dependentCD4bs-specific mAb.
Journal ArticleDOI
Population pharmacokinetics analysis of VRC01, an HIV-1 broadly neutralizing monoclonal antibody, in healthy adults
Yunda Huang,Lily Zhang,Julie E. Ledgerwood,Nicole Grunenberg,Robert T. Bailer,Abby Isaacs,Kelly E. Seaton,Kenneth H. Mayer,Edmund V. Capparelli,Lawrence Corey,Peter B. Gilbert +10 more
TL;DR: A population pharmacokinetics analysis based on 1117 VRC01 serum concentrations using a 2-compartment PK model with first-order elimination is critical for future dose-regimen selection and modeling research to identify VRC 01 serum concentration levels sufficient for protection against HIV infection.
Journal ArticleDOI
A New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo
Natalia T. Freund,Joshua A. Horwitz,Lilian Nogueira,Stuart A. Sievers,Louise Scharf,Johannes F. Scheid,Anna Gazumyan,Cassie Liu,Klara Velinzon,Ariel Goldenthal,Rogier W. Sanders,John P. Moore,Pamela J. Bjorkman,Michael S. Seaman,Bruce D. Walker,Florian Klein,Michel C. Nussenzweig +16 more
TL;DR: It is reported that 179NC75 is highly active when administered to HIV-1-infected humanized mice, where it selects for escape variants that lack a glycan site at position-276, implying that the antibody also exerts selection pressure in humans.
Journal ArticleDOI
Nef Decreases HIV-1 Sensitivity to Neutralizing Antibodies that Target the Membrane-proximal External Region of TMgp41
Rachel P. J. Lai,Jin Yan,Jonathan L. Heeney,Myra McClure,Heinrich G. Göttlinger,Jeremy Luban,Massimo Pizzato,Massimo Pizzato +7 more
TL;DR: It is demonstrated that Nef protects lentiviruses from one of the most broadly-acting classes of neutralizing antibodies and has important implications for anti-HIV-1 immunity and AIDS pathogenesis.
Journal ArticleDOI
Structural Vaccinology for Viral Vaccine Design.
Mohd Ishtiaq Anasir,Chit Laa Poh +1 more
TL;DR: This review focuses on recent advances in structure-based vaccine design, or structural vaccinology, for novel and innovative viral vaccine design.
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
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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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