title: Anti-retroviral antibody FcγR-mediated effector functions.
abstract: The antiviral activity of antibodies reflects the bifunctional properties of these molecules. While the Fab domains mediate highly specific antigenic recognition to block virus entry, the Fc domain interacts with diverse types of Fcγ receptors (FcγRs) expressed on the surface of effector leukocytes to induce the activation of distinct immunomodulatory pathways. Fc-FcγR interactions are tightly regulated to control IgG-mediated inflammation and immunity and are largely determined by the structural heterogeneity of the IgG Fc domain, stemming from differences in the primary amino acid sequence of the various subclasses, as well as the structure and composition of the Fc-associated N-linked glycan. Engagement of specific FcγR types on effector leukocytes has diverse consequences that affect several aspects of innate and adaptive immunity. In this review, we provide an overview of the complexity of FcγR-mediated pathways, discussing their role in the in vivo protective activity of anti-HIV-1 antibodies. We focus on recent studies on broadly neutralizing anti-HIV-1 antibodies that revealed that Fc-FcγR interactions are required to achieve full therapeutic activity through clearance of IgG-opsonized virions and elimination of HIV-infected cells. Manipulation of Fc-FcγR interactions to specifically activate distinct FcγR-mediated pathways has the potential to affect downstream effector responses, influencing thereby the in vivo protective activity of anti-HIV-1 antibodies; a strategy that has already been successfully applied to other IgG-based therapeutics, substantially improving their clinical efficacy.
authors.affiliation: The Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY, USA.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Bournazos
authors.affiliation: The Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY, USA.
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D015483:HIV Antibodies / Q000276:immunology* / Q000627:therapeutic use; D015658:HIV Infections / Q000276:immunology / Q000628:therapy*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D056747:Immunomodulation; D007167:Immunotherapy / Q000379:methods*; D010587:Phagocytosis; D017452:Receptors, IgG / Q000276:immunology; D019562:Viral Load
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007140:Immunoglobulin Fab Fragments; D017452:Receptors, IgG
keywords: 
  AIDS
  ; Fc receptors; antibodies; cytotoxicity; immunotherapies; inflammation