HIV-specific Fc effector function early in infection predicts the development of broadly neutralizing antibodies

Abstract

While the induction of broadly neutralizing antibodies (bNAbs) is a major goal of HIV vaccination strategies, there is mounting evidence to suggest that antibodies with Fc effector function also contribute to protection against HIV infection. Here we investigated Fc effector functionality of HIV-specific IgG plasma antibodies over 3 years of infection in 23 individuals, 13 of whom developed bNAbs. Antibody-dependent cellular phagocytosis (ADCP), complement deposition (ADCD), cellular cytotoxicity (ADCC) and cellular trogocytosis (ADCT) were detected in almost all individuals with levels of activity increasing over time. At 6 months post-infection, individuals with bNAbs had significantly higher levels of ADCD and ADCT that correlated with antibody binding to C1q and FcγRIIa respectively. In addition, antibodies from individuals with bNAbs showed more IgG subclass diversity to multiple HIV antigens which also correlated with Fc polyfunctionality. Germinal center activity represented by CXCL13 levels and expression of activation-induced cytidine deaminase (AID) was found to be associated with neutralization breadth, Fc polyfunctionality and IgG subclass diversity. Overall, multivariate analysis by random forest classification was able to group bNAb individuals with 85% sensitivity and 80% specificity based on the properties of their antibody Fc early in HIV infection. Thus, the Fc effector function profile predicted the development of neutralization breadth in this cohort, suggesting that intrinsic immune factors within the germinal center provide a mechanistic link between the Fc and Fab of HIV-specific antibodies.

Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk

“…The association of FcγRIIa binding with HIV-1 risk also remained significant in the IgA interaction model (OR = 0.405 [IgA -], P = 0.001; OR = 0.682 [IgA + ], P = 0.002) with the interaction P value being 0.200. Env IgG3 breadth is a weight-systemic HIV-1 infection, including clearance of virions that may decrease the number of functionally infectious virions to infect new cells and phagocytosis or trogocytosis of infected cells (54,55) that may limit their capacity to produce and spread new virions. Although our analysis showed no impact from IgG3, timing of exposure may be important to any impact on VL due to the rapid decline of Env IgG3 following vaccination (47).…”

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

“…This protection may be particularly efficient when several Fc-mediated activities are combined (158). Fc polyfunctionality increases over time following HIV infection and has recently been correlated with the further induction of neutralizing activity (195).…”

An Inflammatory Story: Antibodies in Tuberculosis Comorbidities

“…ADCC responses to Env have been associated with improved clinical outcomes and places mutation pressure on HIV-1 virus (196,199,(201)(202)(203). While historically HIV studies have focused upon NK cell mediated ADCC, recent research has demonstrated the importance of other Fc functions mediated by neutrophils, macrophages, monocytes, and complement activation (204,205), such that polyfunctional antibody responses may be beneficial (172,206,207). Through the strong engagement of these particular Fc receptors in HIV infection, cells are activated resulting in downstream release of inflammatory cytokines and cytotoxic granules.…”