Polyclonal B Cell Responses to Conserved Neutralization Epitopes in a Subset of HIV-1-Infected Individuals
Georgia D. Tomaras,James M. Binley,Elin S. Gray,Emma T. Crooks,Keiko Osawa,Penny L. Moore,Nancy Tumba,Tommy Tong,Xiaoying Shen,Nicole L. Yates,Julie Decker,Constantinos Kurt Wibmer,Feng Gao,S. Munir Alam,Philippa Easterbrook,Salim S. Abdool Karim,Gift Kamanga,John A. Crump,Myron S. Cohen,George M. Shaw,John R. Mascola,Barton F. Haynes,David C. Montefiori,Lynn Morris +23 more
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TLDR
The broadly reactive HIV-1 neutralization observed in some subjects is mediated by antibodies targeting several conserved regions on the HIV- 1 envelope glycoprotein.Abstract:
A small proportion of HIV-infected individuals generate a neutralizing antibody (NAb) response of exceptional magnitude and breadth. A detailed analysis of the critical epitopes targeted by broadly neutralizing antibodies should help to define optimal targets for vaccine design. HIV-1-infected subjects with potent cross-reactive serum neutralizing antibodies were identified by assaying sera from 308 subjects against a multiclade panel of 12 “tier 2” viruses (4 each of subtypes A, B, and C). Various neutralizing epitope specificities were determined for the top 9 neutralizers, including clade A-, clade B-, clade C-, and clade A/C-infected donors, by using a comprehensive set of assays. In some subjects, neutralization breadth was mediated by two or more antibody specificities. Although antibodies to the gp41 membrane-proximal external region (MPER) were identified in some subjects, the subjects with the greatest neutralization breadth targeted gp120 epitopes, including the CD4 binding site, a glycan-containing quaternary epitope formed by the V2 and V3 loops, or an outer domain epitope containing a glycan at residue N332. The broadly reactive HIV-1 neutralization observed in some subjects is mediated by antibodies targeting several conserved regions on the HIV-1 envelope glycoprotein.read more
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Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus
Hua-Xin Liao,Rebecca M. Lynch,Tongqing Zhou,Feng Gao,Feng Gao,S. Munir Alam,S. Munir Alam,Scott D. Boyd,Andrew Fire,Krishna M. Roskin,Chaim A. Schramm,Zhenhai Zhang,Jiang Zhu,Lawrence Shapiro,Lawrence Shapiro,Nisc Comparative Sequencing Program,James C. Mullikin,Sandrasegaram Gnanakaran,Peter T. Hraber,Kevin Wiehe,Kevin Wiehe,Garnett Kelsoe,Garnett Kelsoe,Guang Yang,Guang Yang,Shi-Mao Xia,Shi-Mao Xia,David C. Montefiori,David C. Montefiori,Robert Parks,Robert Parks,Krissey E. Lloyd,Krissey E. Lloyd,Richard M. Scearce,Richard M. Scearce,Kelly A. Soderberg,Kelly A. Soderberg,Myron S. Cohen,Gift Kamanga,Mark K. Louder,Lillian Tran,Yue Chen,Yue Chen,Fangping Cai,Fangping Cai,Sheri Chen,Sheri Chen,Stephanie Moquin,Xiulian Du,M. Gordon Joyce,Sanjay Srivatsan,Baoshan Zhang,Anqi Zheng,George M. Shaw,Beatrice H. Hahn,Thomas B. Kepler,Bette T. Korber,Peter D. Kwong,John R. Mascola,Barton F. Haynes,Barton F. Haynes +60 more
TL;DR: The isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection and its co-crystal structure revealed a new loop-based mechanism of CD4-binding-site recognition.
Journal ArticleDOI
Broad and potent neutralization of HIV-1 by a gp41-specific human antibody
Jinghe Huang,Gilad Ofek,Leo B. Laub,Mark K. Louder,Nicole A. Doria-Rose,Nancy S. Longo,Hiromi Imamichi,Robert T. Bailer,Bimal K. Chakrabarti,Shailendra Kumar Sharma,S. Munir Alam,Tao Wang,Yongping Yang,Baoshan Zhang,Stephen A. Migueles,Richard T. Wyatt,Barton F. Haynes,Peter D. Kwong,John R. Mascola,Mark Connors +19 more
TL;DR: The structure of 10E8 in complex with the complete MPER revealed a site of vulnerability comprising a narrow stretch of highly conserved gp41-hydrophobic residues and a critical arginine or lysine just before the transmembrane region, suggesting the importance of these residues for neutralization.
Journal ArticleDOI
Structure and immune recognition of trimeric pre-fusion HIV-1 Env
Marie Pancera,Tongqing Zhou,Aliaksandr Druz,Ivelin S. Georgiev,Cinque Soto,Jason Gorman,Jinghe Huang,Priyamvada Acharya,Gwo-Yu Chuang,Gilad Ofek,Guillaume Stewart-Jones,Jonathan Stuckey,Robert T. Bailer,M. Gordon Joyce,Mark K. Louder,Nancy Tumba,Yongping Yang,Baoshan Zhang,Myron S. Cohen,Barton F. Haynes,John R. Mascola,Lynn Morris,James B. Munro,Scott C. Blanchard,Walther Mothes,Mark Connors,Peter D. Kwong +26 more
TL;DR: The structure at 3.5 Å resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22 is reported, revealing the pre-fusion conformation of gp41, rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition.
Journal ArticleDOI
Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies.
Hugo Mouquet,Louise Scharf,Zelda Euler,Yan Liu,Caroline Eden,Johannes F. Scheid,Johannes F. Scheid,Ariel Halper-Stromberg,Priyanthi N. P. Gnanapragasam,Daniel I. R. Spencer,Michael S. Seaman,Hanneke Schuitemaker,Ten Feizi,Michel C. Nussenzweig,Pamela J. Bjorkman +14 more
TL;DR: As HIV envelopes exhibit varying proportions of high-mannose- and complex-type N-glycans, these results suggest promiscuous carbohydrate interactions, an advantageous adaptation ensuring neutralization of all viruses within a given strain.
Journal ArticleDOI
B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study
TL;DR: The isolation of BnAbs from HIV-1–infected subjects and the use of computationally derived clonal lineages as templates provide a new path for HIV- 1 vaccine immunogen design, which should be applicable to many infectious agents and holds promise for the construction of vaccines that can drive B cells along rare but desirable maturation pathways.
References
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Journal ArticleDOI
Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1
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TL;DR: 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.
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Journal ArticleDOI
Rapid evolution of the neutralizing antibody response to HIV type 1 infection
TL;DR: Plasma virus continually and rapidly evolved to escape neutralization, indicating that neutralizing antibody exerts a level of selective pressure that has been underappreciated based on earlier, less comprehensive characterizations.
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