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    Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals.

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    Date
    2010-01-20
    Authors
    Balla-Jhagjhoorsingh, S
    Corti, D
    Davis, D
    Dreja, H
    Fernandez-Rodriguez, BM
    Heeney, JL
    Hinz, A
    Jarrossay, D
    Jeffs, SA
    Langedijk, JPM
    Lanzavecchia, A
    McKnight, A
    Montefiori, David Charles
    O'Sullivan, E
    Orkin, C
    Pade, C
    Pinna, D
    Sallusto, F
    Sattentau, QJ
    Seaman, MS
    Silacci, C
    Vanzetta, F
    Weiss, RA
    Weissenhorn, W
    Willems, B
    Zekveld, MJ
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    Abstract
    BACKGROUND: The isolation of human monoclonal antibodies (mAbs) that neutralize a broad spectrum of primary HIV-1 isolates and the characterization of the human neutralizing antibody B cell response to HIV-1 infection are important goals that are central to the design of an effective antibody-based vaccine. METHODS AND FINDINGS: We immortalized IgG(+) memory B cells from individuals infected with diverse clades of HIV-1 and selected on the basis of plasma neutralization profiles that were cross-clade and relatively potent. Culture supernatants were screened using various recombinant forms of the envelope glycoproteins (Env) in multiple parallel assays. We isolated 58 mAbs that were mapped to different Env surfaces, most of which showed neutralizing activity. One mAb in particular (HJ16) specific for a novel epitope proximal to the CD4 binding site on gp120 selectively neutralized a multi-clade panel of Tier-2 HIV-1 pseudoviruses, and demonstrated reactivity that was comparable in breadth, but distinct in neutralization specificity, to that of the other CD4 binding site-specific neutralizing mAb b12. A second mAb (HGN194) bound a conserved epitope in the V3 crown and neutralized all Tier-1 and a proportion of Tier-2 pseudoviruses tested, irrespective of clade. A third mAb (HK20) with broad neutralizing activity, particularly as a Fab fragment, recognized a highly conserved epitope in the HR-1 region of gp41, but showed striking assay-dependent selectivity in its activity. CONCLUSIONS: This study reveals that by using appropriate screening methods, a large proportion of memory B cells can be isolated that produce mAbs with HIV-1 neutralizing activity. Three of these mAbs show unusual breadth of neutralization and therefore add to the current panel of HIV-1 neutralizing antibodies with potential for passive protection and template-based vaccine design.
    Type
    Journal article
    Subject
    Amino Acid Sequence
    Antibodies, Monoclonal
    Antibodies, Neutralizing
    Antigens, CD4
    B-Lymphocytes
    Binding Sites, Antibody
    Epitopes
    HIV Infections
    HIV-1
    Humans
    Immunologic Memory
    Molecular Sequence Data
    Permalink
    https://hdl.handle.net/10161/4523
    Published Version (Please cite this version)
    10.1371/journal.pone.0008805
    Publication Info
    Balla-Jhagjhoorsingh, S; Corti, D; Davis, D; Dreja, H; Fernandez-Rodriguez, BM; Heeney, JL; ... Zekveld, MJ (2010). Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals. PLoS One, 5(1). pp. e8805. 10.1371/journal.pone.0008805. Retrieved from https://hdl.handle.net/10161/4523.
    This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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    Scholars@Duke

    Montefiori

    David Charles Montefiori

    Professor of Surgery
    Dr. Montefiori is Professor and Director of the Laboratory for AIDS Vaccine Research and Development in the Department of Surgery, Division of Surgical Sciences, Duke University Medical Center. His major research interests are viral immunology and AIDS vaccine development, with a special emphasis on neutralizing antibodies. One of his highest priorities is to identify immunogens that generate broadly cross-reactive neutralizing antibodies for inclusion in HIV vaccines.  Many aspects of the
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