Update on Fc-Mediated Antibody Functions Against HIV-1 Beyond Neutralization

Abstract

Antibodies (Abs) are the major component of the humoral immune response and a key player in vaccination. The precise Ab-mediated inhibitory mechanisms leading to in vivo protection against HIV have not been elucidated. In addition to the desired viral capture and neutralizing Ab functions, complex Ab-dependent mechanisms that involve engaging immune effector cells to clear infected host cells, immune complexes, and opsonized virus have been proposed as being relevant. These inhibitory mechanisms involve Fc-mediated effector functions leading to Ab-dependent cellular cytotoxicity, phagocytosis, cell-mediated virus inhibition, aggregation, and complement inhibition. Indeed, the decreased risk of infection observed in the RV144 HIV-1 vaccine trial was correlated with the production of non-neutralizing inhibitory Abs, highlighting the role of Ab inhibitory functions besides neutralization. Moreover, Ab isotypes and subclasses recognizing specific HIV envelope epitopes as well as pecular Fc-receptor polymorphisms have been associated with disease progression. These findings further support the need to define which Fc-mediated Ab inhibitory functions leading to protection are critical for HIV vaccine design. Herein, based on our previous review Su & Moog Front Immunol 2014, we update the different inhibitory properties of HIV-specific Abs that may potentially contribute to HIV protection.

Keywords: ADCC; FcR-mediated inhibition; HIV-1; antibody functions; non-neutralizing antibodies.

Figure 1

Distinct inhibitory activities of Abs in HIV target cells. The interaction of Fc regions with Fc gamma receptors (FcγRs) on immune cells, such as dendritic cells (DCs), macrophages, and natural killer (NK) cells, will trigger several antiviral immune responses, including immune activation, which are able to restrain HIV replication. Five major Ab responses against HIV infection that can occur as a result of IgG neutralizing Abs (depicted in red), IgG non-neutralizing inhibitory Abs (depicted in blue) or IgA (in green) are shown. (A) There are two types of stratified epithelium and columnar epithelium. The binding of virus/Ab immune complexes to FcRn at the surfaces of Langerhans cells may lead to transcytosis through genitorectal mucosal surfaces; (B) FcγRIII-mediated antibody-dependent cellular cytotoxicity (ADCC); (C) neutralizing antibody (NAb)-mediated activity; (D) phagocytosis mediated by NAbs/non-NAbs through FcγRI binding; (E) FcγRII-mediated non-neutralizing inhibition; some FcγR/Fc interactions may also enhance HIV entry and infection. These different inhibitory activities can occur at mucosal sites beneath the mono- or pluri-stratified epithelial layers where HIV target cells reside.

Figure 2

Human FcγR gene polymorphisms and the expression and affinity of IgG subtypes. Four IgG subtypes are present in human serum that have distinct structures and functions (top). FcγRs belong to the Ig receptor superfamily and comprise two or three extracellular Ig domains that mediate IgG binding. Differential immune regulatory effects are produced depending on binding to FcRs. Activating or inhibitory functions occur based on the presence of an intracellular cytoplasmic domain ITAM or ITIM motif that transduces an immunostimulatory or inhibitory signal, respectively, following receptor cross-linking. Binding of the Fc to the receptors is mediated at the CH2-CH3 interface following a conformational change (right). The diversity of FcγRs is further increased by SNPs in their extracellular domains, which in turn affect the expression of FcRs and their binding affinity and function (bottom). Mo, Monocyte; Mϕ, Macrophage; DC, Dendritic cell; MC, Mast cell; Neu, Neutrophil; Bas, Basophil; Eos, Eosinophil; NK, Natural killer cell; BC, B cell; PLT, Platelet.