17 results on '"Staupe RP"'
Search Results
2. Development of high titer anti-drug antibodies in a Phase 1b/2a infant clesrovimab trial are associated with RSV exposure beyond day 150.
- Author
-
Thambi N, Phuah JY, Staupe RP, Tobias LM, Cao Y, McKelvey T, Railkar RA, Aliprantis AO, Arriola CS, Maas BM, and Vora KA
- Abstract
Background: Clesrovimab is a human half-life extended mAb in phase 3 evaluation for the prevention of RSV disease in infants. ADA were observed at late time points in a phase 1b/2a study where clesrovimab was well tolerated with an extended half-life of ∼45 days., Methods: Serum samples at days 150, 365 and 545 post-dose were assayed for ADA titers. Samples with high ADA titers were characterized for their binding specificity to the Fab or the YTE portion of clesrovimab. RSV serum neutralization (SNA) titers were also measured on ADA+ and ADA- infants. Additionally, a D25 (site Ø) competitive ELISA was performed on ADA+ available samples to determine RSV exposure. Local surveillance data was used to ascertain RSV circulation during the trial., Results: High ADA titers were observed in a minority of infants at days 365 and 545 for all doses tested. Additionally, all high titer ADA+ infants had ADA directed towards the YTE epitope of clesrovimab. Moreover, these infants demonstrated robust RSV-SNA and had D25 competitive antibodies suggesting an RSV exposure after day 150, coinciding with the epidemiological data., Conclusion: RSV exposure in infants beyond day 150 after dosing is associated with ADA development and high RSV-SNA titers with no impact on pharmacokinetics., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
- Published
- 2024
- Full Text
- View/download PDF
3. In vitro modeling of CD8 + T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40.
- Author
-
Wu JE, Manne S, Ngiow SF, Baxter AE, Huang H, Freilich E, Clark ML, Lee JH, Chen Z, Khan O, Staupe RP, Huang YJ, Shi J, Giles JR, and Wherry EJ
- Subjects
- CD8-Positive T-Lymphocytes, Cell Differentiation, Epigenomics, Clustered Regularly Interspaced Short Palindromic Repeats genetics, T-Cell Exhaustion
- Abstract
Identifying molecular mechanisms of exhausted CD8 T cells (T
ex ) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo Tex can be costly and inefficient. In vitro models of Tex are easily customizable and quickly generate high cellular yield, enabling CRISPR screening and other high-throughput assays. We established an in vitro model of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fide in vivo Tex . We leveraged this model of in vitro chronic stimulation in combination with CRISPR screening to identify transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40. In vitro and in vivo validation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate Tex subsets. By developing and benchmarking an in vitro model of Tex , then applying high-throughput CRISPR screening, we demonstrate the utility of mechanistically annotated in vitro models of Tex .- Published
- 2023
- Full Text
- View/download PDF
4. In Vitro Modeling of CD8 T Cell Exhaustion Enables CRISPR Screening to Reveal a Role for BHLHE40.
- Author
-
Wu JE, Manne S, Ngiow SF, Baxter AE, Huang H, Freilich E, Clark ML, Lee JH, Chen Z, Khan O, Staupe RP, Huang YJ, Shi J, Giles JR, and Wherry EJ
- Abstract
Identifying novel molecular mechanisms of exhausted CD8 T cells (T
ex ) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo Tex can be costly and inefficient. In vitro models of Tex are easily customizable and quickly generate high cellular yield, offering an opportunity to perform CRISPR screening and other high-throughput assays. We established an in vitro model of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fide in vivo Tex . We leveraged this model of in vitro chronic stimulation in combination with pooled CRISPR screening to uncover transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40. In vitro and in vivo validation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate subsets of Tex . By developing and benchmarking an in vitro model of Tex , we demonstrate the utility of mechanistically annotated in vitro models of Tex , in combination with high-throughput approaches, as a discovery pipeline to uncover novel Tex biology.- Published
- 2023
- Full Text
- View/download PDF
5. Single cell multi-omic reference atlases of non-human primate immune tissues reveals CD102 as a biomarker for long-lived plasma cells.
- Author
-
Staupe RP, Lodge KE, Thambi N, Toole D, Tamburino AM, Chang D, Howell BJ, Hazuda DJ, Vora KA, and Sullivan NL
- Subjects
- Mice, Animals, Antibody Formation, Antibodies, Primates, Biomarkers, Plasma Cells, Multiomics
- Abstract
In response to infection or immunization, antibodies are produced that provide protection against re-exposure with the same pathogen. These antibodies can persist at high titers for decades and are maintained by bone marrow-resident long-lived plasma cells (LLPC). However, the durability of antibody responses to immunization varies amongst vaccines. It is unknown what factors contribute to the differential longevity of serum antibody responses and whether heterogeneity in LLPC contributes to this phenomenon. While LLPC differentiation has been studied extensively in mice, little is known about this population in humans or non-human primates (NHP). Here, we use multi-omic single-cell profiling to identify and characterize the LLPC compartment in NHP. We identify LLPC biomarkers including the marker CD102 and show that CD102 in combination with CD31 identifies LLPC in NHP bone marrow. Additionally, we find that CD102 is expressed by LLPC in mouse and humans. These results further our understanding of the LLPC compartment in NHP, identify biomarkers of LLPC, and provide tissue-specific single cell references for future studies., (© 2022. Merck & Co., Inc., Rahway, NJ, USA and its affiliates.)
- Published
- 2022
- Full Text
- View/download PDF
6. PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine.
- Author
-
Herati RS, Knorr DA, Vella LA, Silva LV, Chilukuri L, Apostolidis SA, Huang AC, Muselman A, Manne S, Kuthuru O, Staupe RP, Adamski SA, Kannan S, Kurupati RK, Ertl HCJ, Wong JL, Bournazos S, McGettigan S, Schuchter LM, Kotecha RR, Funt SA, Voss MH, Motzer RJ, Lee CH, Bajorin DF, Mitchell TC, Ravetch JV, and Wherry EJ
- Subjects
- Adult, Humans, Immunity, Humoral, Seasons, T-Lymphocytes, Helper-Inducer, Vaccination, Influenza Vaccines
- Abstract
Anti-programmed death-1 (anti-PD-1) immunotherapy reinvigorates CD8 T cell responses in patients with cancer but PD-1 is also expressed by other immune cells, including follicular helper CD4 T cells (Tfh) which are involved in germinal centre responses. Little is known, however, about the effects of anti-PD-1 immunotherapy on noncancer immune responses in humans. To investigate this question, we examined the impact of anti-PD-1 immunotherapy on the Tfh-B cell axis responding to unrelated viral antigens. Following influenza vaccination, a subset of adults receiving anti-PD-1 had more robust circulating Tfh responses than adults not receiving immunotherapy. PD-1 pathway blockade resulted in transcriptional signatures of increased cellular proliferation in circulating Tfh and responding B cells compared with controls. These latter observations suggest an underlying change in the Tfh-B cell and germinal centre axis in a subset of immunotherapy patients. Together, these results demonstrate dynamic effects of anti-PD-1 therapy on influenza vaccine responses and highlight analytical vaccination as an approach that may reveal underlying immune predisposition to adverse events., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2022
- Full Text
- View/download PDF
7. Role of nuclear localization in the regulation and function of T-bet and Eomes in exhausted CD8 T cells.
- Author
-
McLane LM, Ngiow SF, Chen Z, Attanasio J, Manne S, Ruthel G, Wu JE, Staupe RP, Xu W, Amaravadi RK, Xu X, Karakousis GC, Mitchell TC, Schuchter LM, Huang AC, Freedman BD, Betts MR, and Wherry EJ
- Subjects
- Animals, Cell Differentiation, Humans, Mice, Signal Transduction, CD8-Positive T-Lymphocytes metabolism, T-Box Domain Proteins metabolism
- Abstract
The transcription factors T-bet and Eomesodermin (Eomes) regulate CD8 T cell exhaustion through undefined mechanisms. Here, we show that the subcellular localization of T-bet and Eomes dictate their regulatory activity in exhausted T cells (T
EX s). TEX s had a higher ratio of nuclear Eomes:T-bet than memory T cells (TMEM s) during chronic lymphocytic choriomeningitis virus (LCMV) infection in preclinical cancer models and in human tumors. Biochemically, T-bet and Eomes compete for the same DNA sequences, including the Pdcd1 T-box. High nuclear T-bet strongly represses Pdcd1 transcription in TMEM , whereas low nuclear T-bet in TEX leads to a dominant effect of Eomes that acts as a weaker repressor of Pdcd1. Blocking PD-1 signaling in TEX s increases nuclear T-bet, restoring stronger repression of Pdcd1, and driving T-bet-associated gene expression programs of chemotaxis, homing, and activation. These data identify a mechanism whereby the T-bet-Eomes axis regulates exhaustion through their nuclear localization, providing insights into how these transcription factors regulate TEX biology., Competing Interests: Declaration of interests E.J.W. has consulting agreements with and/or is on the scientific advisory board for Merck, Elstar, Janssen, Related Sciences, Synthekine, and Surface Oncology. E.J.W. is a founder of Surface Oncology and Arsenal Biosciences. E.J.W. has a patent licensing agreement on the PD-1 pathway with Roche/Genentech., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
8. TCF-1-Centered Transcriptional Network Drives an Effector versus Exhausted CD8 T Cell-Fate Decision.
- Author
-
Chen Z, Ji Z, Ngiow SF, Manne S, Cai Z, Huang AC, Johnson J, Staupe RP, Bengsch B, Xu C, Yu S, Kurachi M, Herati RS, Vella LA, Baxter AE, Wu JE, Khan O, Beltra JC, Giles JR, Stelekati E, McLane LM, Lau CW, Yang X, Berger SL, Vahedi G, Ji H, and Wherry EJ
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, Cell Differentiation genetics, Cell Differentiation immunology, Chronic Disease, Gene Expression Profiling, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Mice, Programmed Cell Death 1 Receptor metabolism, T Cell Transcription Factor 1 genetics, Virus Diseases genetics, Virus Diseases immunology, Virus Diseases virology, CD8-Positive T-Lymphocytes metabolism, Gene Regulatory Networks, T Cell Transcription Factor 1 metabolism, Transcription, Genetic
- Abstract
TCF-1 is a key transcription factor in progenitor exhausted CD8 T cells (Tex). Moreover, this Tex cell subset mediates responses to PD-1 checkpoint pathway blockade. However, the role of the transcription factor TCF-1 in early fate decisions and initial generation of Tex cells is unclear. Single-cell RNA sequencing (scRNA-seq) and lineage tracing identified a TCF-1
+ Ly108+ PD-1+ CD8 T cell population that seeds development of mature Tex cells early during chronic infection. TCF-1 mediated the bifurcation between divergent fates, repressing development of terminal KLRG1Hi effectors while fostering KLRG1Lo Tex precursor cells, and PD-1 stabilized this TCF-1+ Tex precursor cell pool. TCF-1 mediated a T-bet-to-Eomes transcription factor transition in Tex precursors by promoting Eomes expression and drove c-Myb expression that controlled Bcl-2 and survival. These data define a role for TCF-1 in early-fate-bifurcation-driving Tex precursor cells and also identify PD-1 as a protector of this early TCF-1 subset., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
9. TOX transcriptionally and epigenetically programs CD8 + T cell exhaustion.
- Author
-
Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, Werner MT, Huang AC, Alexander KA, Wu JE, Attanasio J, Yan P, George SM, Bengsch B, Staupe RP, Donahue G, Xu W, Amaravadi RK, Xu X, Karakousis GC, Mitchell TC, Schuchter LM, Kaye J, Berger SL, and Wherry EJ
- Subjects
- Animals, Calcineurin metabolism, Calcium Signaling, Feedback, Physiological, Female, Gene Expression Regulation immunology, Genotype, Immunologic Memory, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, NFATC Transcription Factors metabolism, Tumor Escape, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Epistasis, Genetic, Homeodomain Proteins metabolism, Transcription, Genetic
- Abstract
Exhausted CD8
+ T (Tex ) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff ) or memory (Tmem ) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program.- Published
- 2019
- Full Text
- View/download PDF
10. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.
- Author
-
Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, Xu W, Harmon S, Giles JR, Wenz B, Adamow M, Kuk D, Panageas KS, Carrera C, Wong P, Quagliarello F, Wubbenhorst B, D'Andrea K, Pauken KE, Herati RS, Staupe RP, Schenkel JM, McGettigan S, Kothari S, George SM, Vonderheide RH, Amaravadi RK, Karakousis GC, Schuchter LM, Xu X, Nathanson KL, Wolchok JD, Gangadhar TC, and Wherry EJ
- Subjects
- Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized immunology, Antibodies, Monoclonal, Humanized pharmacokinetics, Antibodies, Monoclonal, Humanized therapeutic use, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes metabolism, Female, Humans, Ki-67 Antigen immunology, Ki-67 Antigen metabolism, Male, Melanoma blood supply, Melanoma pathology, Neoplasm Staging, Phenotype, Treatment Outcome, CD8-Positive T-Lymphocytes immunology, Melanoma drug therapy, Melanoma immunology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Tumor Burden immunology
- Abstract
Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (T
ex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.- Published
- 2017
- Full Text
- View/download PDF
11. Cutting Edge: B Cell-Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection.
- Author
-
Barnett BE, Staupe RP, Odorizzi PM, Palko O, Tomov VT, Mahan AE, Gunn B, Chen D, Paley MA, Alter G, Reiner SL, Lauer GM, Teijaro JR, and Wherry EJ
- Subjects
- Animals, Cell Separation, Chronic Disease, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Immunoglobulin G immunology, Lymphocytic choriomeningitis virus, Mice, Mice, Transgenic, Oligonucleotide Array Sequence Analysis, B-Lymphocyte Subsets immunology, B-Lymphocytes immunology, Lymphocytic Choriomeningitis immunology, T-Box Domain Proteins immunology
- Abstract
The role of Ab and B cells in preventing infection is established. In contrast, the role of B cell responses in containing chronic infections remains poorly understood. IgG2a (IgG1 in humans) can prevent acute infections, and T-bet promotes IgG2a isotype switching. However, whether IgG2a and B cell-expressed T-bet influence the host-pathogen balance during persisting infections is unclear. We demonstrate that B cell-specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells controlled IgG2a production, as well as mucosal localization, proliferation, glycosylation, and a broad transcriptional program. T-bet controlled a broad antiviral program in addition to IgG2a because T-bet in B cells was important, even in the presence of virus-specific IgG2a. Our data support a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages., (Copyright © 2016 by The American Association of Immunologists, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
12. Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody.
- Author
-
Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, Ploquin A, Doria-Rose NA, Staupe RP, Bailey M, Shi W, Choe M, Marcus H, Thompson EA, Cagigi A, Silacci C, Fernandez-Rodriguez B, Perez L, Sallusto F, Vanzetta F, Agatic G, Cameroni E, Kisalu N, Gordon I, Ledgerwood JE, Mascola JR, Graham BS, Muyembe-Tamfun JJ, Trefry JC, Lanzavecchia A, and Sullivan NJ
- Subjects
- Adult, Animals, Antibodies, Monoclonal immunology, Antibodies, Monoclonal isolation & purification, Antibodies, Neutralizing immunology, Antibodies, Neutralizing isolation & purification, Antibodies, Viral immunology, Antibodies, Viral isolation & purification, Clinical Trials as Topic, Disease Outbreaks, Female, Hemorrhagic Fever, Ebola epidemiology, Humans, Macaca, Male, Molecular Sequence Data, Survivors, Antibodies, Monoclonal administration & dosage, Antibodies, Neutralizing administration & dosage, Antibodies, Viral administration & dosage, Ebolavirus immunology, Hemorrhagic Fever, Ebola prevention & control
- Abstract
Ebola virus disease in humans is highly lethal, with case fatality rates ranging from 25 to 90%. There is no licensed treatment or vaccine against the virus, underscoring the need for efficacious countermeasures. We ascertained that a human survivor of the 1995 Kikwit Ebola virus disease outbreak maintained circulating antibodies against the Ebola virus surface glycoprotein for more than a decade after infection. From this survivor we isolated monoclonal antibodies (mAbs) that neutralize recent and previous outbreak variants of Ebola virus and mediate antibody-dependent cell-mediated cytotoxicity in vitro. Strikingly, monotherapy with mAb114 protected macaques when given as late as 5 days after challenge. Treatment with a single human mAb suggests that a simplified therapeutic strategy for human Ebola infection may be possible., (Copyright © 2016, American Association for the Advancement of Science.)
- Published
- 2016
- Full Text
- View/download PDF
13. New Member of the V1V2-Directed CAP256-VRC26 Lineage That Shows Increased Breadth and Exceptional Potency.
- Author
-
Doria-Rose NA, Bhiman JN, Roark RS, Schramm CA, Gorman J, Chuang GY, Pancera M, Cale EM, Ernandes MJ, Louder MK, Asokan M, Bailer RT, Druz A, Fraschilla IR, Garrett NJ, Jarosinski M, Lynch RM, McKee K, O'Dell S, Pegu A, Schmidt SD, Staupe RP, Sutton MS, Wang K, Wibmer CK, Haynes BF, Abdool-Karim S, Shapiro L, Kwong PD, Moore PL, Morris L, and Mascola JR
- Subjects
- Antibodies, Neutralizing genetics, Antibodies, Neutralizing isolation & purification, Epitope Mapping, Female, HIV Antibodies genetics, HIV Antibodies isolation & purification, HIV Envelope Protein gp120 immunology, Humans, Inhibitory Concentration 50, Molecular Sequence Data, Sequence Analysis, DNA, Antibodies, Neutralizing immunology, Cross Reactions, HIV Antibodies immunology, HIV Infections immunology, HIV Infections virology, HIV-1 immunology
- Abstract
Unlabelled: The epitopes defined by HIV-1 broadly neutralizing antibodies (bNAbs) are valuable templates for vaccine design, and studies of the immunological development of these antibodies are providing insights for vaccination strategies. In addition, the most potent and broadly reactive of these bNAbs have potential for clinical use. We previously described a family of 12 V1V2-directed neutralizing antibodies, CAP256-VRC26, isolated from an HIV-1 clade C-infected donor at years 1, 2, and 4 of infection (N. A. Doria-Rose et al., Nature 509:55-62, 2014, http://dx.doi.org/10.1038/nature13036). Here, we report on the isolation and characterization of new members of the family mostly obtained at time points of peak serum neutralization breadth and potency. Thirteen antibodies were isolated from B cell culture, and eight were isolated using trimeric envelope probes for differential single B cell sorting. One of the new antibodies displayed a 10-fold greater neutralization potency than previously published lineage members. This antibody, CAP256-VRC26.25, neutralized 57% of diverse clade viral isolates and 70% of clade C isolates with remarkable potency. Among the viruses neutralized, the median 50% inhibitory concentration was 0.001 μg/ml. All 33 lineage members targeted a quaternary epitope focused on V2. While all known bNAbs targeting the V1V2 region interact with the N160 glycan, the CAP256-VRC26 antibodies showed an inverse correlation of neutralization potency with dependence on this glycan. Overall, our results highlight the ongoing evolution within a single antibody lineage and describe more potent and broadly neutralizing members with potential clinical utility, particularly in areas where clade C is prevalent., Importance: Studies of HIV-1 broadly neutralizing antibodies (bNAbs) provide valuable information for vaccine design, and the most potent and broadly reactive of these bNAbs have potential for clinical use. We previously described a family of V1V2-directed neutralizing antibodies from an HIV-1 clade C-infected donor. Here, we report on the isolation and characterization of new members of the family mostly obtained at time points of peak serum neutralization breadth and potency. One of the new antibodies, CAP256-VRC26.25, displayed a 10-fold greater neutralization potency than previously described lineage members. It neutralized 57% of diverse clade viral isolates and 70% of clade C isolates with remarkable potency: the median 50% inhibitory concentration was 0.001 μg/ml. Our results highlight the ongoing evolution within a single antibody lineage and describe more potent and broadly neutralizing members with potential clinical utility, particularly in areas where clade C is prevalent., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
- Full Text
- View/download PDF
14. Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies.
- Author
-
Doria-Rose NA, Schramm CA, Gorman J, Moore PL, Bhiman JN, DeKosky BJ, Ernandes MJ, Georgiev IS, Kim HJ, Pancera M, Staupe RP, Altae-Tran HR, Bailer RT, Crooks ET, Cupo A, Druz A, Garrett NJ, Hoi KH, Kong R, Louder MK, Longo NS, McKee K, Nonyane M, O'Dell S, Roark RS, Rudicell RS, Schmidt SD, Sheward DJ, Soto C, Wibmer CK, Yang Y, Zhang Z, Mullikin JC, Binley JM, Sanders RW, Wilson IA, Moore JP, Ward AB, Georgiou G, Williamson C, Abdool Karim SS, Morris L, Kwong PD, Shapiro L, and Mascola JR
- Subjects
- AIDS Vaccines chemistry, AIDS Vaccines immunology, Amino Acid Sequence, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing genetics, Antibodies, Neutralizing isolation & purification, Antibody Affinity genetics, Antibody Affinity immunology, B-Lymphocytes cytology, B-Lymphocytes immunology, B-Lymphocytes metabolism, Binding Sites immunology, CD4 Antigens immunology, CD4 Antigens metabolism, Cell Lineage, Complementarity Determining Regions chemistry, Complementarity Determining Regions genetics, Complementarity Determining Regions immunology, Epitope Mapping, Epitopes, B-Lymphocyte chemistry, Epitopes, B-Lymphocyte immunology, Evolution, Molecular, HIV Antibodies chemistry, HIV Antibodies genetics, HIV Antibodies isolation & purification, HIV Infections immunology, HIV-1 chemistry, HIV-1 immunology, Humans, Models, Molecular, Molecular Sequence Data, Neutralization Tests, Protein Structure, Tertiary, Somatic Hypermutation, Immunoglobulin genetics, Antibodies, Neutralizing immunology, HIV Antibodies immunology, HIV Envelope Protein gp160 chemistry, HIV Envelope Protein gp160 immunology
- Abstract
Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30-38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development.
- Published
- 2014
- Full Text
- View/download PDF
15. Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16.
- Author
-
Pancera M, Shahzad-Ul-Hussan S, Doria-Rose NA, McLellan JS, Bailer RT, Dai K, Loesgen S, Louder MK, Staupe RP, Yang Y, Zhang B, Parks R, Eudailey J, Lloyd KE, Blinn J, Alam SM, Haynes BF, Amin MN, Wang LX, Burton DR, Koff WC, Nabel GJ, Mascola JR, Bewley CA, and Kwong PD
- Subjects
- Amino Acid Motifs, Amino Acid Sequence, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing metabolism, Antibody Specificity, Antigen-Antibody Reactions, Binding Sites, Antibody, Carbohydrate Conformation, Carbohydrate Sequence, Crystallography, X-Ray, Epitopes chemistry, Epitopes immunology, Epitopes metabolism, Glycosylation drug effects, HEK293 Cells, HIV Antibodies chemistry, HIV Antibodies metabolism, HIV Envelope Protein gp120 chemistry, HIV Envelope Protein gp120 metabolism, Humans, Immunoglobulin Fab Fragments immunology, Immunoglobulin Fab Fragments metabolism, Models, Molecular, Molecular Sequence Data, Peptide Fragments chemistry, Peptide Fragments metabolism, Polysaccharides chemistry, Polysaccharides metabolism, Protein Conformation, Protein Processing, Post-Translational drug effects, Structure-Activity Relationship, Swainsonine pharmacology, Antibodies, Neutralizing immunology, HIV Antibodies immunology, HIV Envelope Protein gp120 immunology, Peptide Fragments immunology, Polysaccharides immunology
- Abstract
HIV-1 uses a diverse N-linked-glycan shield to evade recognition by antibody. Select human antibodies, such as the clonally related PG9 and PG16, recognize glycopeptide epitopes in the HIV-1 V1-V2 region and penetrate this shield, but their ability to accommodate diverse glycans is unclear. Here we report the structure of antibody PG16 bound to a scaffolded V1-V2, showing an epitope comprising both high mannose-type and complex-type N-linked glycans. We combined structure, NMR and mutagenesis analyses to characterize glycan recognition by PG9 and PG16. Three PG16-specific residues, arginine, serine and histidine (RSH), were critical for binding sialic acid on complex-type glycans, and introduction of these residues into PG9 produced a chimeric antibody with enhanced HIV-1 neutralization. Although HIV-1-glycan diversity facilitates evasion, antibody somatic diversity can overcome this and can provide clues to guide the design of modified antibodies with enhanced neutralization.
- Published
- 2013
- Full Text
- View/download PDF
16. Delineating antibody recognition in polyclonal sera from patterns of HIV-1 isolate neutralization.
- Author
-
Georgiev IS, Doria-Rose NA, Zhou T, Kwon YD, Staupe RP, Moquin S, Chuang GY, Louder MK, Schmidt SD, Altae-Tran HR, Bailer RT, McKee K, Nason M, O'Dell S, Ofek G, Pancera M, Srivatsan S, Shapiro L, Connors M, Migueles SA, Morris L, Nishimura Y, Martin MA, Mascola JR, and Kwong PD
- Subjects
- Animals, Antibodies, Neutralizing blood, Epitope Mapping, HIV Antibodies blood, HIV Infections blood, HIV-1 isolation & purification, Humans, Immunodominant Epitopes chemistry, Immunodominant Epitopes immunology, Macaca, Neutralization Tests, Protein Conformation, Serum immunology, Antibodies, Neutralizing immunology, HIV Antibodies immunology, HIV Infections immunology, HIV-1 immunology
- Abstract
Serum characterization and antibody isolation are transforming our understanding of the humoral immune response to viral infection. Here, we show that epitope specificities of HIV-1-neutralizing antibodies in serum can be elucidated from the serum pattern of neutralization against a diverse panel of HIV-1 isolates. We determined "neutralization fingerprints" for 30 neutralizing antibodies on a panel of 34 diverse HIV-1 strains and showed that similarity in neutralization fingerprint correlated with similarity in epitope. We used these fingerprints to delineate specificities of polyclonal sera from 24 HIV-1-infected donors and a chimeric siman-human immunodeficiency virus-infected macaque. Delineated specificities matched published specificities and were further confirmed by antibody isolation for two sera. Patterns of virus-isolate neutralization can thus afford a detailed epitope-specific understanding of neutralizing-antibody responses to viral infection.
- Published
- 2013
- Full Text
- View/download PDF
17. A short segment of the HIV-1 gp120 V1/V2 region is a major determinant of resistance to V1/V2 neutralizing antibodies.
- Author
-
Doria-Rose NA, Georgiev I, O'Dell S, Chuang GY, Staupe RP, McLellan JS, Gorman J, Pancera M, Bonsignori M, Haynes BF, Burton DR, Koff WC, Kwong PD, and Mascola JR
- Subjects
- Amino Acid Sequence, Antibodies, Neutralizing immunology, HIV Antibodies immunology, HIV Envelope Protein gp120 immunology, HIV-1 immunology, Humans, Structure-Activity Relationship, Antibodies, Neutralizing chemistry, HIV Antibodies chemistry, HIV Envelope Protein gp120 chemistry, HIV-1 chemistry
- Abstract
Antibody PG9 is a prototypical member of a class of V1/V2-directed antibodies that effectively neutralizes diverse strains of HIV-1. We analyzed strain-specific resistance to PG9 using sequence and structural information. For multiply resistant strains, mutations in a short segment of V1/V2 resulted in gain of sensitivity to PG9 and related V1/V2 neutralizing antibodies, suggesting both a common mechanism of HIV-1 resistance to and a common mode of recognition by this class of antibodies.
- Published
- 2012
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.