A panel of IgG1 b12 variants with selectively diminished or enhanced affinity for Fcγ receptors to define the role of effector functions in protection against HIV

Brian Moldt, Niccole Schultz, D. Cameron Dunlop, Michael D. Alpert, Jackson D. Harvey, David T. Evans, Pascal Poignard, Ann Hessell, Dennis R. Burton

    Research output: Contribution to journalArticle

    42 Citations (Scopus)

    Abstract

    Passive transfer of neutralizing antibodies is effective in protecting rhesus macaques against simian/human immunodeficiency virus (SHIV) challenge. In addition to neutralization, effector functions of the crystallizable fragment (Fc) of antibodies are involved in antibody-mediated protection against a number of viruses. We recently showed that interaction between the Fc fragment of the broadly neutralizing antibody IgG1 b12 and cellular Fcγ receptors (FcγRs) plays an important role in protection against SHIV infection in rhesus macaques. The specific nature of this Fc-dependent protection is largely unknown. To investigate, we generated a panel of 11 IgG1 b12 antibody variants with selectively diminished or enhanced affinity for the two main activating FcγRs, FcγRIIa and FcγRIIIa. All 11 antibody variants bind gp120 and neutralize virus as effectively as does wild-type b12. Binding studies using monomeric (enzyme-linked immunosorbent assay [ELISA] and surface plasmon resonance [SPR]) and cellularly expressed Fcγ receptors show decreased (up to 5-fold) and increased (up to 90-fold) binding to FcγRIIa and FcγRIIIa with this newly generated panel of antibodies. In addition, there was generally a good correlation between b12 variant affinity for Fcγ receptor and variant function in antibody-dependent cell-mediated virus inhibition (ADCVI), phagocytosis, NK cell activation assays, and antibody-dependent cellular cytotoxicity (ADCC) assays. In future studies, these b12 variants will enable the investigation of the protective role of individual FcγRs in HIV infection.

    Original languageEnglish (US)
    Pages (from-to)10572-10581
    Number of pages10
    JournalJournal of Virology
    Volume85
    Issue number20
    DOIs
    StatePublished - Oct 2011

    Fingerprint

    Fc Receptors
    Immunoglobulin G
    HIV
    receptors
    antibodies
    Antibodies
    Immunoglobulin Fc Fragments
    Simian Immunodeficiency Virus
    Viruses
    Neutralizing Antibodies
    Macaca mulatta
    HIV infections
    neutralizing antibodies
    viruses
    Immunoglobulin Fragments
    Surface Plasmon Resonance
    surface plasmon resonance
    Virus Diseases
    Phagocytosis
    Natural Killer Cells

    ASJC Scopus subject areas

    • Immunology
    • Virology

    Cite this

    A panel of IgG1 b12 variants with selectively diminished or enhanced affinity for Fcγ receptors to define the role of effector functions in protection against HIV. / Moldt, Brian; Schultz, Niccole; Dunlop, D. Cameron; Alpert, Michael D.; Harvey, Jackson D.; Evans, David T.; Poignard, Pascal; Hessell, Ann; Burton, Dennis R.

    In: Journal of Virology, Vol. 85, No. 20, 10.2011, p. 10572-10581.

    Research output: Contribution to journalArticle

    Moldt, Brian ; Schultz, Niccole ; Dunlop, D. Cameron ; Alpert, Michael D. ; Harvey, Jackson D. ; Evans, David T. ; Poignard, Pascal ; Hessell, Ann ; Burton, Dennis R. / A panel of IgG1 b12 variants with selectively diminished or enhanced affinity for Fcγ receptors to define the role of effector functions in protection against HIV. In: Journal of Virology. 2011 ; Vol. 85, No. 20. pp. 10572-10581.
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