There is increasing evidence to suggest that antibodies with Fc effector functions can protect against HIV infection together with broadly neutralising antibodies (bNAbs). The authors therefore investigated the Fc effector functionality of HIV-specific IgG antibodies over 3 years of infection in 23 HIV-infected patients, 13 of whom developed bNAbs. The authors noted antibody-dependent cellular phagocytosis (ADCP), complement deposition (ADCD), cellular cytotoxicity (ADCC) and cellular trogocytosis (ADCT) in almost all patients, with levels of activity increasing over time. By 6 months post-infection, patients with bNAbs had significantly higher levels of ADCD and ADCT that correlated with antibody binding to C1q and FcγRIIa, respectively. Antibodies from patients with bNAbs also displayed more IgG subclass diversity to multiple HIV antigens, which also correlated with Fc polyfunctionality. Germinal centre activity, represented by CXCL13 levels and expression of activation-induced cytidine deaminase (AID), was found to be associated with the breadth of neutralisation, Fc polyfunctionality and IgG subclass diversity. Multivariate analysis could group bNAb patients with 85% sensitivity and 80% specificity based on the properties of their antibody Fc early in HIV infection. Therefore it appears that Fc effector function profiles can predict the development of neutralisation breadth in this cohort, with intrinsic immune factors within the germinal centre providing a mechanistic link between the Fc and Fab of HIV-specific antibodies.
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