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  1. Article ; Online: Health Economic Aspects of Chimeric Antigen Receptor T-cell Therapies for Hematological Cancers: Present and Future.

    Heine, Renaud / Thielen, Frederick W / Koopmanschap, Marc / Kersten, Marie José / Einsele, Hermann / Jaeger, Ulrich / Sonneveld, Pieter / Sierra, Jorge / Smand, Carin / Uyl-de Groot, Carin A

    HemaSphere

    2021  Volume 5, Issue 2, Page(s) e524

    Abstract: Since 2018, 2 chimeric antigen receptor (CAR) T-cell therapies received approval from the European Medicine Agency, with list prices around 320 000 Euro (€) (EUR) per treatment. These high prices raise concerns for patient access and the sustainability ... ...

    Abstract Since 2018, 2 chimeric antigen receptor (CAR) T-cell therapies received approval from the European Medicine Agency, with list prices around 320 000 Euro (€) (EUR) per treatment. These high prices raise concerns for patient access and the sustainability of healthcare systems. We aimed to estimate the costs and budget impact associated with CAR T-cell therapies for current and future indications in hematological cancers from 2019 to 2029. We focused on the former France, Germany, Spain, Italy and the United Kingdom (EU-5) and the Netherlands. We conducted a review of list prices, health technology assessment reports, budget impact analysis dossiers, and published cost-effectiveness analyses. We forecasted the 10-year health expenditures on CAR T-cells for several hematological cancers in selected European Union countries. Nine cost-effectiveness studies were identified and list prices for CAR T-cell therapies ranged between 307 200 EUR and 350 000 EUR. Estimated additional costs for pre- and post-treatment were 50 359 EUR per patient, whereas the incremental costs of CAR T-cell therapy (when compared with care as usual) ranged between 276 086 EUR and 328 727 EUR. We estimated market entry of CAR T-cell therapies for chronic mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, multiple myeloma, and acute myeloid leukemia in 2021, 2022, 2022, 2022, and 2025, respectively. Cumulative expenditure estimates for existing and future indications from 2019 to 2029 were on average 28.5 billion EUR, 32.8 billion EUR, and 28.9 billion EUR when considering CAR T-cell therapy costs only, CAR T-cell therapy costs including pre- and post-treatment, and incremental CAR T-cell therapy costs, respectively. CAR T-cell therapies seem to be promising treatment options for hematological cancers but the financial burden on healthcare systems in the former EU-5 and the Netherlands will contribute to a substantial rise in healthcare expenditure in the field of hematology.
    Language English
    Publishing date 2021-01-28
    Publishing country United States
    Document type Journal Article
    ISSN 2572-9241
    ISSN (online) 2572-9241
    DOI 10.1097/HS9.0000000000000524
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Markers of early changes in cognition across cohorts of adults with Down syndrome at risk of Alzheimer's disease.

    Aschenbrenner, Andrew J / Baksh, R Asaad / Benejam, Bessy / Beresford-Webb, Jessica A / Coppus, Antonia / Fortea, Juan / Handen, Benjamin L / Hartley, Sigan / Head, Elizabeth / Jaeger, Judith / Levin, Johannes / Loosli, Sandra V / Rebillat, Anne-Sophie / Sacco, Silvia / Schmitt, Frederick A / Thurlow, Kate E / Zaman, Shahid / Hassenstab, Jason / Strydom, Andre

    Alzheimer's & dementia (Amsterdam, Netherlands)

    2021  Volume 13, Issue 1, Page(s) e12184

    Abstract: Introduction: Down syndrome (DS), a genetic variant of early onset Alzheimer's disease (AD), lacks a suitable outcome measure for prevention trials targeting pre-dementia stages.: Methods: We used cognitive test data collected in several longitudinal ...

    Abstract Introduction: Down syndrome (DS), a genetic variant of early onset Alzheimer's disease (AD), lacks a suitable outcome measure for prevention trials targeting pre-dementia stages.
    Methods: We used cognitive test data collected in several longitudinal aging studies internationally from 312 participants with DS without dementia to identify composites that were sensitive to change over time. We then conducted additional analyses to provide support for the utility of the composites. The composites were presented to an expert panel to determine the most optimal cognitive battery based on predetermined criteria.
    Results: There were common cognitive domains across site composites, which were sensitive to early decline. The final composite consisted of memory, language/executive functioning, selective attention, orientation, and praxis tests.
    Discussion: We have identified a composite that is sensitive to early decline and thus may have utility as an outcome measure in trials to prevent or delay symptoms of AD in DS.
    Language English
    Publishing date 2021-05-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2832898-X
    ISSN 2352-8729
    ISSN 2352-8729
    DOI 10.1002/dad2.12184
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Determinants of Tenascin-C and HIV-1 envelope binding and neutralization.

    Mangan, Riley J / Stamper, Lisa / Ohashi, Tomoo / Eudailey, Joshua A / Go, Eden P / Jaeger, Frederick H / Itell, Hannah L / Watts, Brian E / Fouda, Genevieve G / Erickson, Harold P / Alam, S Munir / Desaire, Heather / Permar, Sallie R

    Mucosal immunology

    2019  Volume 12, Issue 4, Page(s) 1004–1012

    Abstract: Interactions between innate antiviral factors at mucosal surfaces and HIV-1 virions contribute to the natural inefficiency of HIV-1 transmission and are a platform to inform the development of vaccine and nonvaccine strategies to block mucosal HIV-1 ... ...

    Abstract Interactions between innate antiviral factors at mucosal surfaces and HIV-1 virions contribute to the natural inefficiency of HIV-1 transmission and are a platform to inform the development of vaccine and nonvaccine strategies to block mucosal HIV-1 transmission. Tenascin-C (TNC) is a large, hexameric extracellular matrix glycoprotein identified in breast milk and genital fluids that broadly neutralizes HIV-1 via interaction with the HIV-1 Envelope (Env) variable 3 (V3) loop. In this report, we characterize the specific determinants of the interaction between TNC and the HIV-1 Env. We observed that TNC binding and neutralization of HIV-1 is dependent on the TNC fibrinogen-like globe (fbg) and fibronectin-type III (fn) domains, oligomerization, and its newly-mapped glycan structure. Moreover, we observed that TNC-mediated neutralization is also dependent on Env V3 residues 321/322 and 326/327, which surround the IGDIR motif of the V3 loop, as well the N332 glycan, which is critical to the broadly neutralizing activity of glycan-dependent V3-specific antibodies such as PGT128. Our results demonstrate a striking parallel between innate and adaptive immune mechanisms of broad HIV neutralization and provide further insight into the host protein-virus interactions responsible for the natural inefficiency of mucosal HIV-1 transmission.
    MeSH term(s) Amino Acid Sequence ; Amino Acids ; Epitope Mapping ; Epitopes/chemistry ; Epitopes/immunology ; Glycosylation ; HIV Envelope Protein gp120/chemistry ; HIV Envelope Protein gp120/immunology ; HIV Envelope Protein gp120/metabolism ; HIV-1/immunology ; HIV-1/metabolism ; Humans ; Models, Molecular ; Neutralization Tests ; Peptide Fragments/chemistry ; Peptide Fragments/immunology ; Peptide Fragments/metabolism ; Protein Binding ; Protein Conformation ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Recombinant Proteins ; Tenascin/chemistry ; Tenascin/metabolism ; env Gene Products, Human Immunodeficiency Virus/chemistry ; env Gene Products, Human Immunodeficiency Virus/immunology ; env Gene Products, Human Immunodeficiency Virus/metabolism
    Chemical Substances Amino Acids ; Epitopes ; HIV Envelope Protein gp120 ; HIV envelope protein gp120 (305-321) ; Peptide Fragments ; Recombinant Proteins ; Tenascin ; env Gene Products, Human Immunodeficiency Virus
    Language English
    Publishing date 2019-04-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2411370-0
    ISSN 1935-3456 ; 1933-0219
    ISSN (online) 1935-3456
    ISSN 1933-0219
    DOI 10.1038/s41385-019-0164-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Bcl-x

    Hoffmeister-Wittmann, Paula / Mock, Andreas / Nichetti, Federico / Korell, Felix / Heilig, Christoph E / Scherr, Anna-Lena / Günther, Michael / Albrecht, Thomas / Kelmendi, Eblina / Xu, Kaiyu / Nader, Luisa / Kessler, Annika / Schmitt, Nathalie / Fritzsche, Sarah / Weiler, Sofia / Sobol, Benjamin / Stenzinger, Albrecht / Boeck, Stefan / Westphalen, Christoph B /
    Schulze-Osthoff, Klaus / Trojan, Jörg / Kindler, Thomas / Weichert, Wilko / Spiekermann, Karsten / Bitzer, Michael / Folprecht, Gunnar / Illert, Anna L / Boerries, Melanie / Klauschen, Frederick / Ochsenreither, Sebastian / Siveke, Jens / Bauer, Sebastian / Glimm, Hanno / Brors, Benedikt / Hüllein, Jennifer / Hübschmann, Daniel / Uhrig, Sebastian / Horak, Peter / Kreutzfeldt, Simon / Banales, Jesus M / Springfeld, Christoph / Jäger, Dirk / Schirmacher, Peter / Roessler, Stephanie / Ormanns, Steffen / Goeppert, Benjamin / Fröhling, Stefan / Köhler, Bruno C

    Liver international : official journal of the International Association for the Study of the Liver

    2022  Volume 42, Issue 12, Page(s) 2855–2870

    Abstract: Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins ( ...

    Abstract Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-x
    MeSH term(s) Humans ; bcl-X Protein/genetics ; bcl-X Protein/metabolism ; Bile Duct Neoplasms/diagnosis ; Bile Duct Neoplasms/drug therapy ; Bile Ducts, Intrahepatic ; Cell Line, Tumor ; Cholangiocarcinoma/diagnosis ; Cholangiocarcinoma/drug therapy ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Prognosis ; Proto-Oncogene Proteins c-bcl-2/genetics
    Chemical Substances bcl-X Protein ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2
    Language English
    Publishing date 2022-09-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2102783-3
    ISSN 1478-3231 ; 1478-3223
    ISSN (online) 1478-3231
    ISSN 1478-3223
    DOI 10.1111/liv.15392
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The Presence and Anti-HIV-1 Function of Tenascin C in Breast Milk and Genital Fluids.

    Mansour, Robin G / Stamper, Lisa / Jaeger, Frederick / McGuire, Erin / Fouda, Genevieve / Amos, Joshua / Barbas, Kimberly / Ohashi, Tomoo / Alam, S Munir / Erickson, Harold / Permar, Sallie R

    PloS one

    2016  Volume 11, Issue 5, Page(s) e0155261

    Abstract: Tenascin-C (TNC) is a newly identified innate HIV-1-neutralizing protein present in breast milk, yet its presence and potential HIV-inhibitory function in other mucosal fluids is unknown. In this study, we identified TNC as a component of semen and ... ...

    Abstract Tenascin-C (TNC) is a newly identified innate HIV-1-neutralizing protein present in breast milk, yet its presence and potential HIV-inhibitory function in other mucosal fluids is unknown. In this study, we identified TNC as a component of semen and cervical fluid of HIV-1-infected and uninfected individuals, although it is present at a significantly lower concentration and frequency compared to that of colostrum and mature breast milk, potentially due to genital fluid protease degradation. However, TNC was able to neutralize HIV-1 after exposure to low pH, suggesting that TNC could be active at low pH in the vaginal compartment. As mucosal fluids are complex and contain a number of proteins known to interact with the HIV-1 envelope, we further studied the relationship between the concentration of TNC and neutralizing activity in breast milk. The amount of TNC correlated only weakly with the overall innate HIV-1-neutralizing activity of breast milk of uninfected women and negatively correlated with neutralizing activity in milk of HIV-1 infected women, indicating that the amount of TNC in mucosal fluids is not adequate to impede HIV-1 transmission. Moreover, the presence of polyclonal IgG from milk of HIV-1 infected women, but not other HIV-1 envelope-binding milk proteins or monoclonal antibodies, blocked the neutralizing activity of TNC. Finally, as exogenous administration of TNC would be necessary for it to mediate measurable HIV-1 neutralizing activity in mucosal compartments, we established that recombinantly produced TNC has neutralizing activity against transmitted/founder HIV-1 strains that mimic that of purified TNC. Thus, we conclude that endogenous TNC concentration in mucosal fluids is likely inadequate to block HIV-1 transmission to uninfected individuals.
    MeSH term(s) Antibodies, Neutralizing/immunology ; Cervix Uteri/immunology ; Extracellular Fluid/immunology ; Female ; Genitalia ; HIV Antibodies/immunology ; HIV Envelope Protein gp120/immunology ; HIV Envelope Protein gp120/metabolism ; HIV Infections/immunology ; HIV Infections/virology ; HIV-1/drug effects ; HIV-1/immunology ; Humans ; Hydrogen-Ion Concentration ; Immunity, Innate ; Immunoglobulin G/immunology ; Male ; Milk Proteins/immunology ; Milk Proteins/pharmacology ; Milk, Human/immunology ; Mucous Membrane/immunology ; Mucous Membrane/metabolism ; Neutralization Tests ; Peptide Fragments/immunology ; Peptide Fragments/metabolism ; Protein Binding ; Recombinant Proteins ; Semen/immunology ; Tenascin/immunology ; Tenascin/pharmacology
    Chemical Substances Antibodies, Neutralizing ; HIV Antibodies ; HIV Envelope Protein gp120 ; HIV envelope protein gp120 (305-321) ; Immunoglobulin G ; Milk Proteins ; Peptide Fragments ; Recombinant Proteins ; Tenascin
    Language English
    Publishing date 2016-05-16
    Publishing country United States
    Document type Journal Article
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0155261
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The Presence and Anti-HIV-1 Function of Tenascin C in Breast Milk and Genital Fluids.

    Robin G Mansour / Lisa Stamper / Frederick Jaeger / Erin McGuire / Genevieve Fouda / Joshua Amos / Kimberly Barbas / Tomoo Ohashi / S Munir Alam / Harold Erickson / Sallie R Permar

    PLoS ONE, Vol 11, Iss 5, p e

    2016  Volume 0155261

    Abstract: Tenascin-C (TNC) is a newly identified innate HIV-1-neutralizing protein present in breast milk, yet its presence and potential HIV-inhibitory function in other mucosal fluids is unknown. In this study, we identified TNC as a component of semen and ... ...

    Abstract Tenascin-C (TNC) is a newly identified innate HIV-1-neutralizing protein present in breast milk, yet its presence and potential HIV-inhibitory function in other mucosal fluids is unknown. In this study, we identified TNC as a component of semen and cervical fluid of HIV-1-infected and uninfected individuals, although it is present at a significantly lower concentration and frequency compared to that of colostrum and mature breast milk, potentially due to genital fluid protease degradation. However, TNC was able to neutralize HIV-1 after exposure to low pH, suggesting that TNC could be active at low pH in the vaginal compartment. As mucosal fluids are complex and contain a number of proteins known to interact with the HIV-1 envelope, we further studied the relationship between the concentration of TNC and neutralizing activity in breast milk. The amount of TNC correlated only weakly with the overall innate HIV-1-neutralizing activity of breast milk of uninfected women and negatively correlated with neutralizing activity in milk of HIV-1 infected women, indicating that the amount of TNC in mucosal fluids is not adequate to impede HIV-1 transmission. Moreover, the presence of polyclonal IgG from milk of HIV-1 infected women, but not other HIV-1 envelope-binding milk proteins or monoclonal antibodies, blocked the neutralizing activity of TNC. Finally, as exogenous administration of TNC would be necessary for it to mediate measurable HIV-1 neutralizing activity in mucosal compartments, we established that recombinantly produced TNC has neutralizing activity against transmitted/founder HIV-1 strains that mimic that of purified TNC. Thus, we conclude that endogenous TNC concentration in mucosal fluids is likely inadequate to block HIV-1 transmission to uninfected individuals.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Cross-Linking of a CD4-Mimetic Miniprotein with HIV-1 Env gp140 Alters Kinetics and Specificities of Antibody Responses against HIV-1 Env in Macaques.

    Shen, Xiaoying / Bogers, Willy M / Yates, Nicole L / Ferrari, Guido / Dey, Antu K / Williams, William T / Jaeger, Frederick H / Wiehe, Kevin / Sawant, Sheetal / Alam, S Munir / LaBranche, Celia C / Montefiori, David C / Martin, Loic / Srivastava, Indresh / Heeney, Jonathan / Barnett, Susan W / Tomaras, Georgia D

    Journal of virology

    2017  Volume 91, Issue 19

    Abstract: Evaluation of the epitope specificities, locations (systemic or mucosal), and effector functions of antibodies elicited by novel HIV-1 immunogens engineered to improve exposure of specific epitopes is critical for HIV-1 vaccine development. Utilizing an ... ...

    Abstract Evaluation of the epitope specificities, locations (systemic or mucosal), and effector functions of antibodies elicited by novel HIV-1 immunogens engineered to improve exposure of specific epitopes is critical for HIV-1 vaccine development. Utilizing an array of humoral assays, we evaluated the magnitudes, epitope specificities, avidities, and functions of systemic and mucosal immune responses elicited by a vaccine regimen containing Env cross-linked to a CD4-mimetic miniprotein (gp140-M64U1) in rhesus macaques. Cross-linking of gp140 Env to M64U1 resulted in earlier increases of both the magnitude and avidity of the IgG binding response than those with Env protein alone. Notably, IgG binding responses at an early time point correlated with antibody-dependent cellular cytotoxicity (ADCC) function at the peak immunity time point, which was higher for the cross-linked Env group than for the Env group. In addition, the cross-linked Env group developed higher IgG responses against a linear epitope in the gp120 C1 region of the HIV-1 envelope glycoprotein. These data demonstrate that structural modification of the HIV-1 envelope immunogen by cross-linking of gp140 with the CD4-mimetic M64U1 elicited an earlier increase of binding antibody responses and altered the specificity of the IgG responses, correlating with the rise of subsequent antibody-mediated antiviral functions.
    MeSH term(s) AIDS Vaccines/immunology ; Animals ; Antibodies, Neutralizing/immunology ; Antibody-Dependent Cell Cytotoxicity/immunology ; CD4 Antigens/genetics ; CD4 Antigens/immunology ; CD4-Positive T-Lymphocytes/immunology ; Epitopes/immunology ; HIV Antibodies/immunology ; HIV Envelope Protein gp120/immunology ; HIV-1/immunology ; Immunoglobulin A/immunology ; Immunoglobulin G/immunology ; Macaca mulatta/immunology ; Vaccination ; env Gene Products, Human Immunodeficiency Virus/genetics ; env Gene Products, Human Immunodeficiency Virus/immunology
    Chemical Substances AIDS Vaccines ; Antibodies, Neutralizing ; CD4 Antigens ; Epitopes ; HIV Antibodies ; HIV Envelope Protein gp120 ; Immunoglobulin A ; Immunoglobulin G ; env Gene Products, Human Immunodeficiency Virus ; gp140 envelope protein, Human immunodeficiency virus 1
    Language English
    Publishing date 2017-10-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.00401-17
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Modulation of nonneutralizing HIV-1 gp41 responses by an MHC-restricted TH epitope overlapping those of membrane proximal external region broadly neutralizing antibodies.

    Zhang, Jinsong / Alam, S Munir / Bouton-Verville, Hilary / Chen, Yao / Newman, Amanda / Stewart, Shelley / Jaeger, Frederick H / Montefiori, David C / Dennison, S Moses / Haynes, Barton F / Verkoczy, Laurent

    Journal of immunology (Baltimore, Md. : 1950)

    2014  Volume 192, Issue 4, Page(s) 1693–1706

    Abstract: A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs), but current immunization strategies fail to induce BnAbs, and for unknown reasons, often induce nonneutralizing Abs instead. To explore potential host genetic ... ...

    Abstract A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs), but current immunization strategies fail to induce BnAbs, and for unknown reasons, often induce nonneutralizing Abs instead. To explore potential host genetic contributions controlling Ab responses to the HIV-1 Envelope, we have used congenic strains to identify a critical role for MHC class II restriction in modulating Ab responses to the membrane proximal external region (MPER) of gp41, a key vaccine target. Immunized H-2(d)-congenic strains had more rapid, sustained, and elevated MPER(+) Ab titers than those bearing other haplotypes, regardless of immunogen, adjuvant, or prime or boost regimen used, including formulations designed to provide T cell help. H-2(d)-restricted MPER(+) serum Ab responses depended on CD4 TH interactions with class II (as revealed in immunized intra-H-2(d/b) congenic or CD154(-/-) H-2(d) strains, and by selective abrogation of MPER restimulated, H-2(d)-restricted primed splenocytes by class II-blocking Abs), and failed to neutralize HIV-1 in the TZM-b/l neutralization assay, coinciding with lack of specificity for an aspartate residue in the neutralization core of BnAb 2F5. Unexpectedly, H-2(d)-restricted MPER(+) responses functionally mapped to a core TH epitope partially overlapping the 2F5/z13/4E10 BnAb epitopes as well as nonneutralizing B cell-Ab binding residues. We propose that class II restriction contributes to the general heterogeneity of nonneutralizing gp41 responses induced by Envelope. Moreover, the proximity of TH and B cell epitopes in this restriction may have to be considered in redesigning minimal MPER immunogens aimed at exclusively binding BnAb epitopes and triggering MPER(+) BnAbs.
    MeSH term(s) AIDS Vaccines/immunology ; Animals ; Antibodies, Blocking/immunology ; Antibodies, Monoclonal/immunology ; Antibodies, Neutralizing/immunology ; CD40 Ligand/genetics ; Cell Proliferation ; Epitopes, T-Lymphocyte/immunology ; HIV Antibodies/immunology ; HIV Envelope Protein gp41/genetics ; HIV Envelope Protein gp41/immunology ; Histocompatibility Antigens Class II/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; T-Lymphocytes, Helper-Inducer/immunology
    Chemical Substances AIDS Vaccines ; Antibodies, Blocking ; Antibodies, Monoclonal ; Antibodies, Neutralizing ; Epitopes, T-Lymphocyte ; HIV Antibodies ; HIV Envelope Protein gp41 ; Histocompatibility Antigens Class II ; gp41 protein, Human immunodeficiency virus 1 ; CD40 Ligand (147205-72-9)
    Language English
    Publishing date 2014-01-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1302511
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Chemical synthesis of highly congested gp120 V1V2 N-glycopeptide antigens for potential HIV-1-directed vaccines.

    Aussedat, Baptiste / Vohra, Yusuf / Park, Peter K / Fernández-Tejada, Alberto / Alam, S Munir / Dennison, S Moses / Jaeger, Frederick H / Anasti, Kara / Stewart, Shelley / Blinn, Julie H / Liao, Hua-Xin / Sodroski, Joseph G / Haynes, Barton F / Danishefsky, Samuel J

    Journal of the American Chemical Society

    2013  Volume 135, Issue 35, Page(s) 13113–13120

    Abstract: Critical to the search for an effective HIV-1 vaccine is the development of immunogens capable of inducing broadly neutralizing antibodies (BnAbs). A key first step in this process is to design immunogens that can be recognized by known BnAbs. The ... ...

    Abstract Critical to the search for an effective HIV-1 vaccine is the development of immunogens capable of inducing broadly neutralizing antibodies (BnAbs). A key first step in this process is to design immunogens that can be recognized by known BnAbs. The monoclonal antibody PG9 is a BnAb that neutralizes diverse strains of HIV-1 by targeting a conserved carbohydrate-protein epitope in the variable 1 and 2 (V1V2) region of the viral envelope. Important for recognition are two closely spaced N-glycans at Asn(160) and Asn(156). Glycopeptides containing this synthetically challenging bis-N-glycosylated motif were prepared by convergent assembly, and were shown to be antigenic for PG9. Synthetic glycopeptides such as these may be useful for the development of HIV-1 vaccines based on the envelope V1V2 BnAb epitope.
    MeSH term(s) AIDS Vaccines/chemistry ; AIDS Vaccines/immunology ; Antigens/chemistry ; Antigens/immunology ; Carbohydrate Conformation ; Crystallography, X-Ray ; Glycopeptides/chemistry ; Glycopeptides/immunology ; HIV Envelope Protein gp120/chemistry ; HIV Envelope Protein gp120/immunology ; HIV-1/immunology ; Models, Molecular ; Molecular Sequence Data
    Chemical Substances AIDS Vaccines ; Antigens ; Glycopeptides ; HIV Envelope Protein gp120
    Language English
    Publishing date 2013-08-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3155-0
    ISSN 1520-5126 ; 0002-7863
    ISSN (online) 1520-5126
    ISSN 0002-7863
    DOI 10.1021/ja405990z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Structural analysis of the unmutated ancestor of the HIV-1 envelope V2 region antibody CH58 isolated from an RV144 vaccine efficacy trial vaccinee.

    Nicely, Nathan I / Wiehe, Kevin / Kepler, Thomas B / Jaeger, Frederick H / Dennison, S Moses / Rerks-Ngarm, Supachai / Nitayaphan, Sorachai / Pitisuttithum, Punnee / Kaewkungwal, Jaranit / Robb, Merlin L / O'Connell, Robert J / Michael, Nelson L / Kim, Jerome H / Liao, Hua-Xin / Munir Alam, S / Hwang, Kwan-Ki / Bonsignori, Mattia / Haynes, Barton F

    EBioMedicine

    2015  Volume 2, Issue 7, Page(s) 713–722

    Abstract: Human monoclonal antibody CH58 isolated from an RV144 vaccinee binds at Lys169 of the HIV-1 Env gp120 V2 region, a site of vaccine-induced immune pressure. CH58 neutralizes HIV-1 CRF_01 AE strain 92TH023 and mediates ADCC against CD4 + T cell targets ... ...

    Abstract Human monoclonal antibody CH58 isolated from an RV144 vaccinee binds at Lys169 of the HIV-1 Env gp120 V2 region, a site of vaccine-induced immune pressure. CH58 neutralizes HIV-1 CRF_01 AE strain 92TH023 and mediates ADCC against CD4 + T cell targets infected with CRF_01 AE tier 2 virus. CH58 and other antibodies that bind to a gp120 V2 epitope have a second light chain complementarity determining region (LCDR2) bearing a glutamic acid, aspartic acid (ED) motif involved in forming salt bridges with polar, basic side amino acid side chains in V2. In an effort to learn how V2 responses develop, we determined the crystal structures of the CH58-UA antibody unliganded and bound to V2 peptide. The structures showed an LCDR2 structurally pre-conformed from germline to interact with V2 residue Lys169. LCDR3 was subject to conformational selection through the affinity maturation process. Kinetic analyses demonstrate that only a few contacts were responsible for a 2000-fold increase in KD through maturation, and this effect was predominantly due to an improvement in off-rate. This study shows that preconformation and preconfiguration can work in concert to produce antibodies with desired immunogenic properties.
    MeSH term(s) AIDS Vaccines/immunology ; Amino Acid Motifs ; Amino Acid Sequence ; Antibody Affinity/immunology ; Circular Dichroism ; Crystallography, X-Ray ; Epitope Mapping ; HIV Antibodies/immunology ; HIV Antibodies/isolation & purification ; HIV Antigens/chemistry ; HIV Antigens/immunology ; HIV Envelope Protein gp120/chemistry ; HIV Envelope Protein gp120/genetics ; HIV Envelope Protein gp120/immunology ; HIV-1/immunology ; Humans ; Molecular Sequence Data ; Mutation/genetics ; Peptides/chemistry ; Peptides/immunology ; Protein Conformation ; Treatment Outcome
    Chemical Substances AIDS Vaccines ; HIV Antibodies ; HIV Antigens ; HIV Envelope Protein gp120 ; Peptides
    Language English
    Publishing date 2015-06-20
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2851331-9
    ISSN 2352-3964 ; 2352-3964
    ISSN (online) 2352-3964
    ISSN 2352-3964
    DOI 10.1016/j.ebiom.2015.06.016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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