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Increased breadth of HIV-1 neutralization achieved by diverse antibody clones each with limited neutralization breadth.
Chukwuma VU, Kose N, Sather DN, Sapparapu G, Falk R, King H, Singh V, Lampley R, Malherbe DC, Ditto NT, Sullivan JT, Barnes T, Doranz BJ, Labranche CC, Montefiori DC, Kalams SA, Haigwood NL, Crowe JE
(2018) PLoS One 13: e0209437
MeSH Terms: Antibodies, Neutralizing, Antibody Diversity, B-Lymphocytes, Cells, Cultured, Epitope Mapping, Epitopes, HIV Antibodies, HIV Infections, HIV-1, Humans, Hybridomas, Neutralization Tests, env Gene Products, Human Immunodeficiency Virus
Show Abstract · Added March 31, 2019
Broadly neutralizing antibodies (bNAbs) are rarely elicited by current human immunodeficiency virus type 1 (HIV-1) vaccine designs, but the presence of bNAbs in naturally infected individuals may be associated with high plasma viral loads, suggesting that the magnitude, duration, and diversity of viral exposure may contribute to the development of bNAbs. Here, we report the isolation and characterization of a panel of human monoclonal antibodies (mAbs) from two subjects who developed broadly neutralizing autologous antibody responses during HIV-1 infection. In both subjects, we identified collections of mAbs that exhibited specificity only to a few autologous envelopes (Envs), with some mAbs exhibiting specificity only to a subset of Envs within the quasispecies of a particular sample at one time point. Neutralizing antibodies (NAbs) isolated from these subjects mapped mostly to epitopes in the Env V3 loop region and the CD4 binding site. None of the individual neutralizing mAbs recovered exhibited the cumulative breadth of neutralization present in the serum of the subjects. Surprisingly, however, the activity of polyclonal mixtures comprising individual mAbs that each possessed limited neutralizing activity, could achieve increased breadth of neutralizing activity against autologous isolates. While a single broadly neutralizing antibody targeting one epitope can mediate neutralization breadth, the findings presented here suggest that a cooperative polyclonal process mediated by diverse antibodies with more limited breadth targeting multiple epitopes also can achieve neutralization breadth against HIV-1.
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13 MeSH Terms
Broadly Neutralizing Antibody Mediated Clearance of Human Hepatitis C Virus Infection.
Kinchen VJ, Zahid MN, Flyak AI, Soliman MG, Learn GH, Wang S, Davidson E, Doranz BJ, Ray SC, Cox AL, Crowe JE, Bjorkman PJ, Shaw GM, Bailey JR
(2018) Cell Host Microbe 24: 717-730.e5
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibody Specificity, Base Sequence, Binding Sites, Cell Line, Cricetulus, Epitopes, Female, HEK293 Cells, HIV-1, Hepacivirus, Hepatitis C, Hepatitis C Antibodies, Humans, Immunologic Memory, Male, Models, Molecular, Mutagenesis, Site-Directed, Viral Envelope Proteins, Viral Load
Show Abstract · Added March 31, 2019
The role that broadly neutralizing antibodies (bNAbs) play in natural clearance of human hepatitis C virus (HCV) infection and the underlying mechanisms remain unknown. Here, we investigate the mechanism by which bNAbs, isolated from two humans who spontaneously cleared HCV infection, contribute to HCV control. Using viral gene sequences amplified from longitudinal plasma of the two subjects, we found that these bNAbs, which target the front layer of the HCV envelope protein E2, neutralized most autologous HCV strains. Acquisition of resistance to bNAbs by some autologous strains was accompanied by progressive loss of E2 protein function, and temporally associated with HCV clearance. These data demonstrate that bNAbs can mediate clearance of human HCV infection by neutralizing infecting strains and driving escaped viruses to an unfit state. These immunopathologic events distinguish HCV from HIV-1 and suggest that development of an HCV vaccine may be achievable.
Copyright © 2018 Elsevier Inc. All rights reserved.
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22 MeSH Terms
Integrating linear optimization with structural modeling to increase HIV neutralization breadth.
Sevy AM, Panda S, Crowe JE, Meiler J, Vorobeychik Y
(2018) PLoS Comput Biol 14: e1005999
MeSH Terms: Algorithms, Amino Acid Motifs, Antibodies, Neutralizing, Computational Biology, Epitopes, HIV Antibodies, HIV Infections, HIV-1, Humans, Linear Models, Machine Learning, Regression Analysis, Software, Support Vector Machine
Show Abstract · Added March 14, 2018
Computational protein design has been successful in modeling fixed backbone proteins in a single conformation. However, when modeling large ensembles of flexible proteins, current methods in protein design have been insufficient. Large barriers in the energy landscape are difficult to traverse while redesigning a protein sequence, and as a result current design methods only sample a fraction of available sequence space. We propose a new computational approach that combines traditional structure-based modeling using the Rosetta software suite with machine learning and integer linear programming to overcome limitations in the Rosetta sampling methods. We demonstrate the effectiveness of this method, which we call BROAD, by benchmarking the performance on increasing predicted breadth of anti-HIV antibodies. We use this novel method to increase predicted breadth of naturally-occurring antibody VRC23 against a panel of 180 divergent HIV viral strains and achieve 100% predicted binding against the panel. In addition, we compare the performance of this method to state-of-the-art multistate design in Rosetta and show that we can outperform the existing method significantly. We further demonstrate that sequences recovered by this method recover known binding motifs of broadly neutralizing anti-HIV antibodies. Finally, our approach is general and can be extended easily to other protein systems. Although our modeled antibodies were not tested in vitro, we predict that these variants would have greatly increased breadth compared to the wild-type antibody.
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14 MeSH Terms
Surface-Matrix Screening Identifies Semi-specific Interactions that Improve Potency of a Near Pan-reactive HIV-1-Neutralizing Antibody.
Kwon YD, Chuang GY, Zhang B, Bailer RT, Doria-Rose NA, Gindin TS, Lin B, Louder MK, McKee K, O'Dell S, Pegu A, Schmidt SD, Asokan M, Chen X, Choe M, Georgiev IS, Jin V, Pancera M, Rawi R, Wang K, Chaudhuri R, Kueltzo LA, Manceva SD, Todd JP, Scorpio DG, Kim M, Reinherz EL, Wagh K, Korber BM, Connors M, Shapiro L, Mascola JR, Kwong PD
(2018) Cell Rep 22: 1798-1809
MeSH Terms: Antibodies, Neutralizing, Cell Membrane, HIV Antibodies, HIV Envelope Protein gp41, HIV-1, Half-Life, Humans, Neutralization Tests, Polysaccharides, Protein Binding
Show Abstract · Added March 14, 2018
Highly effective HIV-1-neutralizing antibodies could have utility in the prevention or treatment of HIV-1 infection. To improve the potency of 10E8, an antibody capable of near pan-HIV-1 neutralization, we engineered 10E8-surface mutants and screened for improved neutralization. Variants with the largest functional enhancements involved the addition of hydrophobic or positively charged residues, which were positioned to interact with viral membrane lipids or viral glycan-sialic acids, respectively. In both cases, the site of improvement was spatially separated from the region of antibody mediating molecular contact with the protein component of the antigen, thereby improving peripheral semi-specific interactions while maintaining unmodified dominant contacts responsible for broad recognition. The optimized 10E8 antibody, with mutations to phenylalanine and arginine, retained the extraordinary breadth of 10E8 but with ∼10-fold increased potency. We propose surface-matrix screening as a general method to improve antibodies, with improved semi-specific interactions between antibody and antigen enabling increased potency without compromising breadth.
Published by Elsevier Inc.
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10 MeSH Terms
Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models.
Saunders KO, Verkoczy LK, Jiang C, Zhang J, Parks R, Chen H, Housman M, Bouton-Verville H, Shen X, Trama AM, Scearce R, Sutherland L, Santra S, Newman A, Eaton A, Xu K, Georgiev IS, Joyce MG, Tomaras GD, Bonsignori M, Reed SG, Salazar A, Mascola JR, Moody MA, Cain DW, Centlivre M, Zurawski S, Zurawski G, Erickson HP, Kwong PD, Alam SM, Levy Y, Montefiori DC, Haynes BF
(2017) Cell Rep 21: 3681-3690
MeSH Terms: AIDS Vaccines, Amino Acid Sequence, Animals, Antibodies, Neutralizing, Disease Models, Animal, Epitopes, HIV Antibodies, HIV-1, Immunization, Macaca mulatta, Mice, Polysaccharides, Protein Multimerization, Rabbits, env Gene Products, Human Immunodeficiency Virus
Show Abstract · Added March 14, 2018
The events required for the induction of broad neutralizing antibodies (bnAbs) following HIV-1 envelope (Env) vaccination are unknown, and their induction in animal models as proof of concept would be critical. Here, we describe the induction of plasma antibodies capable of neutralizing heterologous primary (tier 2) HIV-1 strains in one macaque and two rabbits. Env immunogens were designed to induce CD4 binding site (CD4bs) bnAbs, but surprisingly, the macaque developed V1V2-glycan bnAbs. Env immunization of CD4bs bnAb heavy chain rearrangement (VDJ) knockin mice similarly induced V1V2-glycan neutralizing antibodies (nAbs), wherein the human CD4bs V chains were replaced with mouse rearrangements bearing diversity region (D)-D fusions, creating antibodies with long, tyrosine-rich HCDR3s. Our results show that Env vaccination can elicit broad neutralization of tier 2 HIV-1, demonstrate that V1V2-glycan bnAbs are more readily induced than CD4bs bnAbs, and define V replacement and diversity region fusion as potential mechanisms for generating V1V2-glycan bnAb site antibodies.
Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
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15 MeSH Terms
Soluble Prefusion Closed DS-SOSIP.664-Env Trimers of Diverse HIV-1 Strains.
Joyce MG, Georgiev IS, Yang Y, Druz A, Geng H, Chuang GY, Kwon YD, Pancera M, Rawi R, Sastry M, Stewart-Jones GBE, Zheng A, Zhou T, Choe M, Van Galen JG, Chen RE, Lees CR, Narpala S, Chambers M, Tsybovsky Y, Baxa U, McDermott AB, Mascola JR, Kwong PD
(2017) Cell Rep 21: 2992-3002
MeSH Terms: AIDS Vaccines, Enzyme-Linked Immunosorbent Assay, HIV-1, Microscopy, Electron, env Gene Products, Human Immunodeficiency Virus
Show Abstract · Added March 14, 2018
The elicitation of autologous neutralizing responses by immunization with HIV-1 envelope (Env) trimers conformationally stabilized in a prefusion closed state has generated considerable interest in the HIV-1 vaccine field. However, soluble prefusion closed Env trimers have been produced from only a handful of HIV-1 strains, limiting their utility as vaccine antigens and B cell probes. Here, we report the engineering from 81 HIV-1 strains of soluble, fully cleaved, prefusion Env trimers with appropriate antigenicity. We used a 96-well expression-screening format to assess the ability of artificial disulfides and Ile559Pro substitution (DS-SOSIP) to produce soluble cleaved-Env trimers; from 180 Env strains, 20 yielded prefusion closed trimers. We also created chimeras, by utilizing structure-based design to incorporate select regions from the well-behaved BG505 strain; from 180 Env strains, 78 DS-SOSIP-stabilized chimeras, including 61 additional strains, yielded prefusion closed trimers. Structure-based design thus enables the production of prefusion closed HIV-1-Env trimers from dozens of diverse strains.
Published by Elsevier Inc.
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5 MeSH Terms
Broadly neutralizing antibodies targeting the HIV-1 envelope V2 apex confer protection against a clade C SHIV challenge.
Julg B, Tartaglia LJ, Keele BF, Wagh K, Pegu A, Sok D, Abbink P, Schmidt SD, Wang K, Chen X, Joyce MG, Georgiev IS, Choe M, Kwong PD, Doria-Rose NA, Le K, Louder MK, Bailer RT, Moore PL, Korber B, Seaman MS, Abdool Karim SS, Morris L, Koup RA, Mascola JR, Burton DR, Barouch DH
(2017) Sci Transl Med 9:
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Neutralizing, CD4-Positive T-Lymphocytes, Female, HIV Envelope Protein gp120, HIV-1, Macaca mulatta, Male, Neutralization Tests, Sequence Alignment, Simian Acquired Immunodeficiency Syndrome, Simian Immunodeficiency Virus, Viral Load
Show Abstract · Added March 14, 2018
Neutralizing antibodies to the V2 apex antigenic region of the HIV-1 envelope (Env) trimer are among the most prevalent cross-reactive antibodies elicited by natural infection. Two recently described V2-specific antibodies, PGDM1400 and CAP256-VRC26.25, have demonstrated exquisite potency and neutralization breadth against HIV-1. However, little data exist on the protective efficacy of V2-specific neutralizing antibodies. We created a novel SHIV-325c viral stock that included a clade C HIV-1 envelope and was susceptible to neutralization by both of these antibodies. Rhesus macaques received a single infusion of either antibody at three different concentrations (2, 0.4, and 0.08 mg/kg) before challenge with SHIV-325c. PGDM1400 was fully protective at the 0.4 mg/kg dose, whereas CAP256-VRC26.25-LS was fully protective even at the 0.08 mg/kg dose, which correlated with its greater in vitro neutralization potency against the challenge virus. Serum antibody concentrations required for protection were <0.75 μg/ml for CAP256-VRC26.25-LS. These data demonstrate unprecedented potency and protective efficacy of V2-specific neutralizing antibodies in nonhuman primates and validate V2 as a potential target for the prevention of HIV-1 infection in passive immunization strategies in humans.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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14 MeSH Terms
Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop.
Cale EM, Gorman J, Radakovich NA, Crooks ET, Osawa K, Tong T, Li J, Nagarajan R, Ozorowski G, Ambrozak DR, Asokan M, Bailer RT, Bennici AK, Chen X, Doria-Rose NA, Druz A, Feng Y, Joyce MG, Louder MK, O'Dell S, Oliver C, Pancera M, Connors M, Hope TJ, Kepler TB, Wyatt RT, Ward AB, Georgiev IS, Kwong PD, Mascola JR, Binley JM
(2017) Immunity 46: 777-791.e10
MeSH Terms: Amino Acid Sequence, Antibodies, Neutralizing, B-Lymphocytes, Binding Sites, Complementarity Determining Regions, HIV Antibodies, HIV Envelope Protein gp120, HIV Infections, HIV-1, Humans, Models, Molecular, Peptide Fragments, Phylogeny, Protein Binding, Protein Conformation, Protein Interaction Domains and Motifs, Protein Multimerization, Vaccines, Virus-Like Particle, env Gene Products, Human Immunodeficiency Virus
Show Abstract · Added March 14, 2018
Most HIV-1-specific neutralizing antibodies isolated to date exhibit unusual characteristics that complicate their elicitation. Neutralizing antibodies that target the V1V2 apex of the HIV-1 envelope (Env) trimer feature unusually long protruding loops, which enable them to penetrate the HIV-1 glycan shield. As antibodies with loops of requisite length are created through uncommon recombination events, an alternative mode of apex binding has been sought. Here, we isolated a lineage of Env apex-directed neutralizing antibodies, N90-VRC38.01-11, by using virus-like particles and conformationally stabilized Env trimers as B cell probes. A crystal structure of N90-VRC38.01 with a scaffolded V1V2 revealed a binding mode involving side-chain-to-side-chain interactions that reduced the distance the antibody loop must traverse the glycan shield, thereby facilitating V1V2 binding via a non-protruding loop. The N90-VRC38 lineage thus identifies a solution for V1V2-apex binding that provides a more conventional B cell pathway for vaccine design.
Copyright © 2017 Elsevier Inc. All rights reserved.
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19 MeSH Terms
Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation.
Zhou T, Doria-Rose NA, Cheng C, Stewart-Jones GBE, Chuang GY, Chambers M, Druz A, Geng H, McKee K, Kwon YD, O'Dell S, Sastry M, Schmidt SD, Xu K, Chen L, Chen RE, Louder MK, Pancera M, Wanninger TG, Zhang B, Zheng A, Farney SK, Foulds KE, Georgiev IS, Joyce MG, Lemmin T, Narpala S, Rawi R, Soto C, Todd JP, Shen CH, Tsybovsky Y, Yang Y, Zhao P, Haynes BF, Stamatatos L, Tiemeyer M, Wells L, Scorpio DG, Shapiro L, McDermott AB, Mascola JR, Kwong PD
(2017) Cell Rep 19: 719-732
MeSH Terms: Animals, Antibodies, Neutralizing, Antibody Specificity, Binding Sites, CD4 Antigens, Crystallography, X-Ray, Epitopes, Glycosylation, Guinea Pigs, HIV Antibodies, HIV-1, Humans, Immunization, Macaca mulatta, Molecular Dynamics Simulation, Polysaccharides, Protein Structure, Quaternary, env Gene Products, Human Immunodeficiency Virus
Show Abstract · Added May 3, 2017
While the HIV-1-glycan shield is known to shelter Env from the humoral immune response, its quantitative impact on antibody elicitation has been unclear. Here, we use targeted deglycosylation to measure the impact of the glycan shield on elicitation of antibodies against the CD4 supersite. We engineered diverse Env trimers with select glycans removed proximal to the CD4 supersite, characterized their structures and glycosylation, and immunized guinea pigs and rhesus macaques. Immunizations yielded little neutralization against wild-type viruses but potent CD4-supersite neutralization (titers 1: >1,000,000 against four-glycan-deleted autologous viruses with over 90% breadth against four-glycan-deleted heterologous strains exhibiting tier 2 neutralization character). To a first approximation, the immunogenicity of the glycan-shielded protein surface was negligible, with Env-elicited neutralization (ID) proportional to the exponential of the protein-surface area accessible to antibody. Based on these high titers and exponential relationship, we propose site-selective deglycosylated trimers as priming immunogens to increase the frequency of site-targeting antibodies.
Published by Elsevier Inc.
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18 MeSH Terms
Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide.
Alam SM, Aussedat B, Vohra Y, Meyerhoff RR, Cale EM, Walkowicz WE, Radakovich NA, Anasti K, Armand L, Parks R, Sutherland L, Scearce R, Joyce MG, Pancera M, Druz A, Georgiev IS, Von Holle T, Eaton A, Fox C, Reed SG, Louder M, Bailer RT, Morris L, Abdool-Karim SS, Cohen M, Liao HX, Montefiori DC, Park PK, Fernández-Tejada A, Wiehe K, Santra S, Kepler TB, Saunders KO, Sodroski J, Kwong PD, Mascola JR, Bonsignori M, Moody MA, Danishefsky S, Haynes BF
(2017) Sci Transl Med 9:
MeSH Terms: Animals, Antibodies, Neutralizing, Antibody Specificity, B-Lymphocytes, Cell Lineage, Cell Separation, Clone Cells, Epitopes, Glycopeptides, HIV Antigens, HIV Envelope Protein gp120, HIV-1, Macaca mulatta, Molecular Mimicry, Protein Domains, Protein Multimerization
Show Abstract · Added May 3, 2017
A goal for an HIV-1 vaccine is to overcome virus variability by inducing broadly neutralizing antibodies (bnAbs). One key target of bnAbs is the glycan-polypeptide at the base of the envelope (Env) third variable loop (V3). We have designed and synthesized a homogeneous minimal immunogen with high-mannose glycans reflective of a native Env V3-glycan bnAb epitope (Man-V3). V3-glycan bnAbs bound to Man-V3 glycopeptide and native-like gp140 trimers with similar affinities. Fluorophore-labeled Man-V3 glycopeptides bound to bnAb memory B cells and were able to be used to isolate a V3-glycan bnAb from an HIV-1-infected individual. In rhesus macaques, immunization with Man-V3 induced V3-glycan-targeted antibodies. Thus, the Man-V3 glycopeptide closely mimics an HIV-1 V3-glycan bnAb epitope and can be used to isolate V3-glycan bnAbs.
Copyright © 2017, American Association for the Advancement of Science.
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16 MeSH Terms