Enhanced Phagocytic Activity of HIV-Specific Antibodies Correlates with Natural Production of Immunoglobulins with Skewed Affinity for FcγR2a and FcγR2b

Abstract

While development of an HIV vaccine that can induce neutralizing antibodies remains a priority, decades of research have proven that this is a daunting task. However, accumulating evidence suggests that antibodies with the capacity to harness innate immunity may provide some protection. While significant research has focused on the cytolytic properties of antibodies in acquisition and control, less is known about the role of additional effector functions. In this study, we investigated antibody-dependent phagocytosis of HIV immune complexes, and we observed significant differences in the ability of antibodies from infected subjects to mediate this critical effector function. We observed both quantitative differences in the capacity of antibodies to drive phagocytosis and qualitative differences in their Fc␥R usage profile. We demonstrate that antibodies from controllers and untreated progressors exhibit increased phagocytic activity, altered Fc domain glycosylation, and skewed interactions with Fc␥R2a and Fc␥R2b in both bulk plasma and HIV-specific IgG. While increased phagocytic activity may directly influence immune activation via clearance of inflammatory immune complexes, it is also plausible that Fc receptor usage patterns may regulate the immune response by modulating downstream signals following phagocytosis-driving passive degradation of internalized virus, release of immune modulating cytokines and chemokines, or priming of a more effective adaptive immune response.

B-cell–independent sialylation of IgG

“…Since then, patient studies support the notion that IgG glycosylation directly impacts function. For autoimmunity, terminal galactosylation (27) and terminal sialylation (2-4, 6) are now established factors in immune modulation, whereas fucosylation has been shown to correlate with antibody-dependent cell-mediated viral inhibition (ADCVI) activity in the context of HIV infection (28,29) as well as antibody-dependent cellular cytotoxicity (ADCC) in vitro (30). For ADCC, structural rearrangements associated with the presence of fucose within the Fc domain appear to account for the functional shift (31), but it remains unclear how fucosylation translates into differential ADCVI activity.…”

Antibody functional assays as measures of Fc receptor-mediated immunity to HIV - new technologies and their impact on the HIV vaccine field.

“…Analysis of the rare HIV-1 infected subjects who naturally completely control viral replication (termed "elite controllers") also illustrate the integral role that ADCC and ADCP play in natural immunity. The trend observed in several studies of natural infection was for higher levels of ADCC antibodies and a response skewed to IgG3/1 subclasses in HIV-1 controllers compared to an IgG4/2 subclass skewing in viremic individuals [18,61,71,72]. ADCC-antibodies are produced more rapidly following infection than neutralizing antibodies, which typically take months or years to develop [46,49].…”

“…Forthal et al (2001) found plasma from acutely infected patients and normal NK effector cells were able to inhibit viral replication, suggesting a role for antibody and NK cells in early control of infection [68]. The assay can use NK cells or monocytes for killing of infected targets [18]. Other formats measured Fc-dependent direct inhibition of replication in primary macrophages [20].…”

“…The normal ligands for cellular FcγR interactions are complexes of IgG and increased complex size increases the avidity of interaction and binding activity [165]. Therefore more functional antigenspecific assays measure binding of complexes to immobilised recombinant soluble receptors [18,166]. For example, recombinant soluble FcγR ectodomains with c-terminal hexahistidine tags have been immobilised on plates via antihexahistidine mAb [166] or nickel [18] to produce an array of receptors for binding IgG ligands.…”

“…Importantly, there is evidence that each activating FcγR can contribute to some protective effects of anti-HIV antibodies (e.g. [18][19][20][21][22][23]). Aggregation of cellular Fc receptors [24], or possibly their reorganisation in the membrane [25] leads to the activation of src family and syk kinases which initiate a cell activation cascade and, depending on the innate cell type, stimulate effector functions such as ADCC and ADCP [1][2][3]26].…”