title: 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.
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.
authors.affiliation: Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Moldt
authors.forename: Niccole
authors.initials: N
authors.lastname: Schultz
authors.forename: D Cameron
authors.initials: DC
authors.lastname: Dunlop
authors.forename: Michael D
authors.initials: MD
authors.lastname: Alpert
authors.forename: Jackson D
authors.initials: JD
authors.lastname: Harvey
authors.forename: David T
authors.initials: DT
authors.lastname: Evans
authors.forename: Pascal
authors.initials: P
authors.lastname: Poignard
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Hessell
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D015483:HIV Antibodies / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology; D008253:Macaca mulatta; D010587:Phagocytosis; D011485:Protein Binding; D011961:Receptors, Fc / Q000276:immunology* / Q000378:metabolism*; D011995:Recombination, Genetic; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology; D020349:Surface Plasmon Resonance
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007074:Immunoglobulin G; D011961:Receptors, Fc