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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Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials.
Peter B. Gilbert,Peter B. Gilbert,Michal Juraska,Allan C. deCamp,Shelly Karuna,Srilatha Edupuganti,Nyaradzo Mgodi,Deborah Donnell,Carter Bentley,Nirupama Sista,Philip Andrew,Abby Isaacs,Yunda Huang,Lily Zhang,Edmund V. Capparelli,Nidhi Kochar,Jing Wang,Susan H. Eshleman,Kenneth H. Mayer,Kenneth H. Mayer,Craig A. Magaret,John Hural,James G. Kublin,Glenda Gray,Glenda Gray,David C. Montefiori,Margarita M Gomez,David N. Burns,J. McElrath,Julie E. Ledgerwood,Barney S. Graham,John R. Mascola,Myron S. Cohen,Lawrence Corey +33 more
TL;DR: The AMP trials test whether VRC01 can prevent HIV-1 infection in two study populations and identify threshold levels of neutralization and Fc effector functions associated with high-level protection, setting a benchmark for future vaccine evaluation and constituting a bridge to other bnAb approaches for HIV- 1 prevention.
Journal ArticleDOI
HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies
Ayub Ali,Scott G. Kitchen,Irvin S. Y. Chen,Hwee L. Ng,Jerome A. Zack,Otto O. Yang,Otto O. Yang +6 more
TL;DR: It is indicated that BNAbs are excellent candidates for developing novel CARs to consider for the immunotherapeutic treatment of HIV-1, and all these CARs are functional against HIV- 1.
Journal ArticleDOI
Identification of Near-Pan-neutralizing Antibodies against HIV-1 by Deconvolution of Plasma Humoral Responses
Mohammad M. Sajadi,Mohammad M. Sajadi,Amir Dashti,Zahra Rikhtegaran Tehrani,Zahra Rikhtegaran Tehrani,William D. Tolbert,Michael S. Seaman,Xin Ouyang,Neelakshi Gohain,Marzena Pazgier,Dongkyoon Kim,Guy Cavet,Jean A. Yared,Robert R. Redfield,George K. Lewis,Anthony L. DeVico +15 more
TL;DR: X-ray crystallographic analysis of one monoclonal suggested a unique ability to bypass the CD4bs Phe43 cavity, while reaching deep into highly conserved residues of Layer 3 of the gp120 inner domain, likely explaining its extreme potency and breadth.
Journal ArticleDOI
Strategies to guide the antibody affinity maturation process.
TL;DR: This work presents immunization strategies that attempt to recapitulate these natural processes and guide the affinity maturation process in order to counteract HIV-1 and influenza viral diversity.
Journal ArticleDOI
Broadly Neutralizing Antibodies for HIV Eradication
TL;DR: This review discusses the application of broadly neutralizing antibodies (bNAbs) for HIV treatment and HIV eradication strategies, and highlights bNAbs that target key epitopes, such as the CD4 binding site and the V2/V3-glycan-dependent sites, and discusses several bNABS that are currently in the clinical development pipeline.
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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