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

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 (Fc?R) 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 Fc?R binding capacity. To investigate antibody-dependent cellular cytotoxicity (ADCC) as a contributor to Fc?R-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 Fc?RIIIa 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 Fc?R-mediated activities distinct from Fc?RIIIa-mediated ADCC may be important in the observed protection against SHIV challenge.

SUBMITTER: Moldt B

PROVIDER: S-EPMC3372207 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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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 B Shibata-Koyama Mami M Rakasz Eva G EG Schultz Niccole N Kanda Yutaka Y Dunlop D Cameron DC Finstad Samantha L SL Jin Chenggang C Landucci Gary G Alpert Michael D MD Dugast Anne-Sophie AS Parren Paul W H I PW Nimmerjahn Falk F Evans David T DT Alter Galit G Forthal Donald N DN Schmitz Jörn E JE Iida Shigeru S Poignard Pascal P Watkins David I DI Hessell Ann J AJ Burton Dennis R DR

Journal of virology 20120328 11

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 ...[more]

PMID: 22457527

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Project description:BackgroundPassive transfer of antibodies can be protective in the simian human immunodeficiency virus (SHIV)--rhesus macaque challenge model. The human monoclonal antibody IgG1 b12 neutralizes human immunodeficiency type 1 (HIV-1) in vitro and protects against challenge by SHIV. Our hypothesis is that neutralizing antibodies can only completely inactivate a relatively small number of infectious virus.Methods and findingsWe have used GHOST cell assays to quantify individual infectious events with HIV-1SF162 and its SHIV derivatives: the relatively neutralization sensitive SHIV(SF162P4) isolate and the more resistant SHIV(SF162P3). A plot of the number of fluorescent GHOST cells with increasing HIV-1SF162 dose is not linear. It is likely that with high-dose inocula, infection with multiple virus produces additive fluorescence in individual cells. In studies of the neutralization kinetics of IgG1 b12 against these isolates, events during the absorption phase of the assay, as well as the incubation phase, determine the level of neutralization. It is possible that complete inactivation of a virus is limited to the time it is exposed on the cell surface. Assays can be modified so that neutralization of these very low doses of virus can be quantified. A higher concentration of antibody is required to neutralize the same dose of resistant SHIV(SF162P3) than the sensitive SHIV(SF162P4). In the absence of selection during passage, the density of the CCR5 co-receptor on the GHOST cell surface is reduced. Changes in the CD4 : CCR5 density ratio influence neutralization.ConclusionsLow concentrations of IgG1 b12 completely inactivate small doses of the neutralization resistant SHIV(SF162P3). Assays need to be modified to quantify this effect. Results from modified assays may predict protection following repeated low-dose shiv challenges in rhesus macaques. It should be possible to induce this level of antibody by vaccination so that modified assays could predict the outcome of human trials.

Dataset Information

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

Publications

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.

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