Fc receptors and the diversity of antibody responses to HIV infection and vaccination

Abstract

The development of an effective vaccine against HIV is desperately needed. The successive failures of HIV vaccine efficacy trials in recent decades have shown the difficulty of inducing an appropriate protective immune response to fight HIV. Different correlates of antibody parameters associated with a decreased risk of HIV-1 acquisition have been identified. However, these parameters are difficult to reproduce and improve, possibly because they have an intricate and combined action. Here, we describe the numerous antibody (Ab) functions associated with HIV-1 protection and report the interrelated parameters regulating their complex functions. Indeed, besides neutralizing and Fc-mediated activity, additional factors such as Ab type, concentration and kinetics of induction, and Fc-receptor expression and binding capacity also influence the protective effect conferred by Abs. As these parameters were described to be associated with ethnicity, age and sex, these additional factors must be considered for the development of an effective immune response. Therefore, future vaccine designs need to consider these multifaceted Ab functions together with the demographic attributes of the patient populations.

Fig. 1. Antibodies and FcR-mediated functions.

A IgG subclasses. B Fc gamma receptors (FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, FcγRIIIb), their main function, polymorphisms, and distribution on immune cells. C FcγR binding affinities of IgG subclasses. CDC complement dependent cytotoxicity, ADCC antibody-dependent cellular cytotoxicity, ADCP antibody-dependent cellular phagocytosis, 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.

Fig. 2. HIV antibody functions.

The functions are dependent on different Ab domains: The Fab domain is involved in virus neutralization, opsonization and aggregation; the Fc domain of Ab induces the activation of the complement system; dual binding of Ab via Fab and Fc domains leads to Fc-mediated antibody function: antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity; FcR internalization may lead to phagocytosis, antigen presentation or antibody-dependent enhancement.