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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Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1
Craig S. Pace,Ruijiang Song,Christina Ochsenbauer,Chasity D. Andrews,David Franco,Jian Yu,Deena A. Oren,Michael S. Seaman,David D. Ho +8 more
TL;DR: It is proposed that iMab-based BibNAbs, such as PG9-iMab and PG16-i Mab, are promising candidates for passive immunization to prevent HIV-1 infection.
Journal ArticleDOI
Bispecific Antibodies Targeting Different Epitopes on the HIV-1 Envelope Exhibit Broad and Potent Neutralization
Mangaiarkarasi Asokan,Rebecca S. Rudicell,Mark K. Louder,Krisha McKee,Sijy O'Dell,Guillaume Stewart-Jones,Keyun Wang,Ling Xu,Xuejun Chen,Misook Choe,Gwo-Yu Chuang,Ivelin S. Georgiev,Michael Gordon Joyce,Tatsiana Kirys,Sung-Youl Ko,Amarendra Pegu,Wei Shi,John-Paul Todd,Zhong-Ning Yang,Robert T. Bailer,Srinivas S. Rao,Peter D. Kwong,Gary J. Nabel,John R. Mascola +23 more
TL;DR: Bispecific antibodies contain the binding specificities of the two parental antibodies and that a single bispecific antibody can neutralize 97% of viral strains with a high overall potency are shown, which support the use of bispespecific antibodies for the prevention or treatment of HIV-1 infection.
Journal ArticleDOI
Epitope specificity of human immunodeficiency virus-1 antibody dependent cellular cytotoxicity [ADCC] responses.
Justin Pollara,Mattia Bonsignori,M. Anthony Moody,Marzena Pazgier,Barton F. Haynes,Guido Ferrari +5 more
TL;DR: The HIV-1 envelope epitopes targeted by ADCC antibodies in the context of the potential protective capacities of ADCC are discussed.
Journal ArticleDOI
Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity
TL;DR: Advances in deconstructing polyclonal antibody responses to flavivirus infection or vaccination are discussed, and comparisons to HIV-1 are drawn.
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The prevention of infection-associated cancers
Silvio De Flora,Paolo Bonanni +1 more
TL;DR: The present article reviews the microbial and parasitic diseases that have been associated so far with human cancers, draws an overview of their burden in cancer epidemiology, deals with applicable prevention strategies and provides examples of co-ordinated approaches to the control of cancers associated with HBV, HCV, HPV, human immunodeficiency virus and H.pylori infections.
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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