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

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.
Author summary Some HIV-infected individuals develop antibodies that are capable of neutralizing the majority of HIV strains, a highly desirable function mediated by the antibody Fab portion. While antibodies elicited by current vaccines have failed to recreate this activity, the partial protection seen in the RV144 vaccine trial has been attributed to antibody Fc-mediated effector functions such as cell killing. In this study, we found that HIV-infected individuals who show a diversified and potent Fc response early in infection were more likely to develop broadly neutralizing antibodies later on. Examination of B cell functions associated with good germinal center activity, provided evidence for a common mechanistic link between the regulation of the Fc and Fab mediated activities in these individuals. Our finding of an Fc effector function profile that arises early and predicts neutralization breadth could be used in the evaluation of vaccine candidates designed to generate neutralizing antibodies. Common immune determinants associated with both Fab and Fc function could furthermore be exploited for vaccine design to harness the full potential of HIV-specific antibodies.