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 Watkins & 2 others Ann J. Hessell, Dennis R. Burton

Research output: Contribution to journalArticle

80 Citations (Scopus)

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
Pages (from-to)6189-6196
Number of pages8
JournalJournal of Virology
Volume86
Issue number11
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

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Simian Immunodeficiency Virus
Human immunodeficiency virus
Macaca
IgG Receptors
Human immunodeficiency virus 1
Antiviral Agents
HIV-1
monoclonal antibodies
Monoclonal Antibodies
HIV
cytotoxicity
receptors
antibodies
Antibodies
neutralization
Immunoglobulin G
binding capacity
Virus Diseases
virus replication
viral load

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

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

In: Journal of Virology, Vol. 86, No. 11, 01.06.2012, p. 6189-6196.

Research output: Contribution to journalArticle

Moldt, B, Shibata-Koyama, M, Rakasz, EG, Schultz, N, Kand, Y, Dunlop, DC, Finstad, SL, Jin, C, Landucci, G, Alpert, MD, Dugast, AS, Parren, PWHI, Nimmerjahn, F, Evans, DT, Alter, G, Forthal, DN, Schmitz, JE, Iida, S, Poignard, P, Watkins, D, Hessell, AJ & Burton, DR 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, vol. 86, no. 11, pp. 6189-6196. https://doi.org/10.1128/JVI.00491-12
Moldt, Brian ; Shibata-Koyama, Mami ; Rakasz, Eva G. ; Schultz, Niccole ; Kand, Yutaka ; Dunlop, D. Cameron ; Finstad, Samantha L. ; Jin, Chenggang ; Landucci, Gary ; Alpert, Michael D. ; Dugast, Anne Sophie ; Parren, Paul W H I ; Nimmerjahn, Falk ; Evans, David T. ; Alter, Galit ; Forthal, Donald N. ; Schmitz, Jörn E. ; Iida, Shigeru ; Poignard, Pascal ; Watkins, David ; Hessell, Ann J. ; Burton, Dennis R. / 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. In: Journal of Virology. 2012 ; Vol. 86, No. 11. pp. 6189-6196.
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AU - Shibata-Koyama, Mami

AU - Rakasz, Eva G.

AU - Schultz, Niccole

AU - Kand, Yutaka

AU - Dunlop, D. Cameron

AU - Finstad, Samantha L.

AU - Jin, Chenggang

AU - Landucci, Gary

AU - Alpert, Michael D.

AU - Dugast, Anne Sophie

AU - Parren, Paul W H I

AU - Nimmerjahn, Falk

AU - Evans, David T.

AU - Alter, Galit

AU - Forthal, Donald N.

AU - Schmitz, Jörn E.

AU - Iida, Shigeru

AU - Poignard, Pascal

AU - Watkins, David

AU - Hessell, Ann J.

AU - Burton, Dennis R.

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