Analysis of a Clonal Lineage of HIV-1 Envelope V2/V3 Conformational Epitope-Specific Broadly Neutralizing Antibodies and Their Inferred Unmutated Common Ancestors
Mattia Bonsignori,Kwan Ki Hwang,Xi Chen,Chun Yen Tsao,Lynn Morris,Elin S. Gray,Dawn J. Marshall,John A. Crump,Saidi Kapiga,Noel E. Sam,Faruk Sinangil,Marie Pancera,Yang Yongping,Baoshan Zhang,Jiang Zhu,Peter D. Kwong,Sijy O'Dell,John R. Mascola,Lan Wu,Gary J. Nabel,Sanjay Phogat,Michael S. Seaman,John F. Whitesides,M. Anthony Moody,Garnett Kelsoe,Xinzhen Yang,Joseph Sodroski,George M. Shaw,David C. Montefiori,Thomas B. Kepler,Georgia D. Tomaras,S. Munir Alam,Hua-Xin Liao,Barton F. Haynes +33 more
TLDR
A clonal lineage of four V2/V3 conformational epitope broadly neutralizing antibodies from an African HIV-1-infected broad neutralizer is identified and their common reverted unmutated ancestor (RUA) antibodies are inferred.Abstract:
V2/V3 conformational epitope antibodies that broadly neutralize HIV-1 (PG9 and PG16) have been recently described. Since an elicitation of previously known broadly neutralizing antibodies has proven elusive, the induction of antibodies with such specificity is an important goal for HIV-1 vaccine development. A critical question is which immunogens and vaccine formulations might be used to trigger and drive the development of memory B cell precursors with V2/V3 conformational epitope specificity. In this paper we identified a clonal lineage of four V2/V3 conformational epitope broadly neutralizing antibodies (CH01 to CH04) from an African HIV-1-infected broad neutralizer and inferred their common reverted unmutated ancestor (RUA) antibodies. While conformational epitope antibodies rarely bind recombinant Env monomers, a screen of 32 recombinant envelopes for binding to the CH01 to CH04 antibodies showed monoclonal antibody (MAb) binding to the E.A244 gp120 Env and to chronic Env AE.CM243; MAbs CH01 and CH02 also bound to transmitted/founder Env B.9021. CH01 to CH04 neutralized 38% to 49% of a panel of 91 HIV-1 tier 2 pseudoviruses, while the RUAs neutralized only 16% of HIV-1 isolates. Although the reverted unmutated ancestors showed restricted neutralizing activity, they retained the ability to bind to the E.A244 gp120 HIV-1 envelope with an affinity predicted to trigger B cell development. Thus, E.A244, B.9021, and AE.CM243 Envs are three potential immunogen candidates for studies aimed at defining strategies to induce V2/V3 conformational epitope-specific antibodies.read more
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Development of therapeutic antibodies for the treatment of diseases
TL;DR: The preeminent antibody engineering technologies used in the development of therapeutic antibody drugs, such as humanization of monoclonal antibodies, phage display, the human antibody mouse, single B cell antibody technology, and affinity maturation are outlined.
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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
Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9
Jason S. McLellan,Marie Pancera,Chris Carrico,Jason Gorman,Jean-Philippe Julien,Reza Khayat,Robert K. Louder,Robert Pejchal,Mallika Sastry,Kaifan Dai,Sijy O'Dell,Nikita Patel,Syed Shahzad-ul-Hussan,Yongping Yang,Baoshan Zhang,Tongqing Zhou,Jiang Zhu,Jeffrey C. Boyington,Gwo-Yu Chuang,Devan Diwanji,Ivelin S. Georgiev,Young Do Kwon,Doyung Lee,Mark K. Louder,Stephanie Moquin,Stephen D. Schmidt,Zhi Yong Yang,Mattia Bonsignori,John A. Crump,John A. Crump,Saidi Kapiga,Noel E. Sam,Barton F. Haynes,Dennis R. Burton,Dennis R. Burton,Wayne C. Koff,Laura M. Walker,Sanjay Phogat,Richard T. Wyatt,Jared Orwenyo,Lai-Xi Wang,James Arthos,Carole A. Bewley,John R. Mascola,Gary J. Nabel,William R. Schief,William R. Schief,Andrew B. Ward,Ian A. Wilson,Peter D. Kwong +49 more
TL;DR: The structure of V1/V2 in complex with PG9 is reported, identifying a paradigm of antibody recognition for highly glycosylated antigens, which—with PG9—involves a site of vulnerability comprising just two glycans and a strand.
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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
Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies.
Nicole A. Doria-Rose,Chaim A. Schramm,Jason Gorman,Penny L. Moore,Jinal N. Bhiman,Brandon J. DeKosky,Michael J. Ernandes,Ivelin S. Georgiev,Helen J. Kim,Marie Pancera,Ryan P. Staupe,Han Altae-Tran,Robert T. Bailer,Ema T. Crooks,Albert Cupo,Aliaksandr Druz,Nigel Garrett,Kam Hon Hoi,Rui Kong,Mark K. Louder,Nancy S. Longo,Krisha McKee,Molati Nonyane,Sijy O'Dell,Ryan S. Roark,Rebecca S. Rudicell,Stephen D. Schmidt,Daniel J. Sheward,Cinque Soto,Constantinos Kurt Wibmer,Yongping Yang,Zhenhai Zhang,Nisc Comparative Sequencing,James C. Mullikin,James M. Binley,Rogier W. Sanders,Ian A. Wilson,John P. Moore,Andrew B. Ward,George Georgiou,Carolyn Williamson,Salim S. Abdool Karim,Lynn Morris,Peter D. Kwong,Lawrence Shapiro,John R. Mascola +45 more
TL;DR: HIV-1 V1V2-directed neutralizing antibodies can develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation, and provide important insights relevant to HIV-1 vaccine development.
References
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The Department of Health and Human Services.
TL;DR: This letter is in response to your two Citizen Petitions, requesting that the Food and Drug Administration (FDA or the Agency) require a cancer warning on cosmetic talc products.
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