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
Open Access
- 15 October 2011
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 85 (20), 10572-10581
- https://doi.org/10.1128/jvi.05541-11
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.This publication has 47 references indexed in Scilit:
- A robust, high-throughput assay to determine the phagocytic activity of clinical antibody samplesJournal of Immunological Methods, 2011
- HIV-1 Replication in Langerhans and Interstitial Dendritic Cells Is Inhibited by Neutralizing and Fc-Mediated Inhibitory AntibodiesJournal of Virology, 2011
- In-Solution Virus Capture Assay Helps Deconstruct Heterogeneous Antibody Recognition of Human Immunodeficiency Virus Type 1Journal of Virology, 2010
- CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain–engineered monoclonal antibodyBlood, 2010
- Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in ThailandThe New England Journal of Medicine, 2009
- The Cat and Mouse of HIV-1 Antibody EscapePLoS Pathogens, 2009
- Fc receptor-mediated antiviral antibodiesCurrent Opinion in HIV and AIDS, 2009
- Utilization of Immunoglobulin G Fc Receptors by Human Immunodeficiency Virus Type 1: a Specific Role for Antibodies against the Membrane-Proximal External Region of gp41Journal of Virology, 2009
- Broadly Neutralizing Human Anti-HIV Antibody 2G12 Is Effective in Protection against Mucosal SHIV Challenge Even at Low Serum Neutralizing TitersPLoS Pathogens, 2009
- Rhesus Macaque Polyclonal and Monoclonal Antibodies Inhibit Simian Immunodeficiency Virus in the Presence of Human or Autologous Rhesus Effector CellsJournal of Virology, 2006