A nonfucosylated variant of the anti-HIV-1 monoclonal antibody b12 has enhanced Fcγriiia-Mediated antiviral activity in vitro but does not improve protection against mucosal SHIV challenge in macaques

Brian Moldt, Mami Shibata-Koyama, Eva G. Rakasz, Niccole Schultz, Yutaka Kand, D. Cameron Dunlop, Samantha L. Finstad, Chenggang Jin, Gary Landucci, Michael D. Alpert, Anne Sophie Dugast, Paul W.H.I. Parren, Falk Nimmerjahn, David T. Evans, Galit Alter, Donald N. Forthal, Jörn E. Schmitz, Shigeru Iida, Pascal Poignard, David I. WatkinsAnn J. Hessell, Dennis R. Burton

    Research output: Contribution to journalArticle

    83 Scopus citations

    Abstract

    Eliciting neutralizing antibodies is thought to be a key activity of a vaccine against human immunodeficiency virus (HIV). However, a number of studies have suggested that in addition to neutralization, interaction of IgG with Fc gamma receptors (FcγR) may play an important role in antibody-mediated protection. We have previously obtained evidence that the protective activity of the broadly neutralizing human IgG1 anti-HIV monoclonal antibody (MAb) b12 in macaques is diminished in the absence of FcγR binding capacity. To investigate antibody-dependent cellular cytotoxicity (ADCC) as a contributor to FcγR-associated protection, we developed a nonfucosylated variant of b12 (NFb12). We showed that, compared to fully fucosylated (referred to as wild-type in the text) b12, NFb12 had higher affinity for human and rhesus macaque FcγRIIIa and was more efficient in inhibiting viral replication and more effective in killing HIV-infected cells in an ADCC assay. Despite these more potent in vitro antiviral activities, NFb12 did not enhance protection in vivo against repeated low-dose vaginal challenge in the simian-human immunodeficiency virus (SHIV)/macaque model compared to wild-type b12. No difference in protection, viral load, or infection susceptibility was observed between animals given NFb12 and those given fully fucosylated b12, indicating that FcγR-mediated activities distinct from FcγRIIIa-mediated ADCC may be important in the observed protection against SHIV challenge.

    Original languageEnglish (US)
    Pages (from-to)6189-6196
    Number of pages8
    JournalJournal of virology
    Volume86
    Issue number11
    DOIs
    StatePublished - Jun 1 2012

    ASJC Scopus subject areas

    • Microbiology
    • Immunology
    • Insect Science
    • Virology

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    Moldt, B., Shibata-Koyama, M., Rakasz, E. G., Schultz, N., Kand, Y., Dunlop, D. C., Finstad, S. L., Jin, C., Landucci, G., Alpert, M. D., Dugast, A. S., Parren, P. W. H. I., Nimmerjahn, F., Evans, D. T., Alter, G., Forthal, D. N., Schmitz, J. E., Iida, S., Poignard, P., ... Burton, D. R. (2012). A nonfucosylated variant of the anti-HIV-1 monoclonal antibody b12 has enhanced Fcγriiia-Mediated antiviral activity in vitro but does not improve protection against mucosal SHIV challenge in macaques. Journal of virology, 86(11), 6189-6196. https://doi.org/10.1128/JVI.00491-12