Abstract
BackgroundThe critical role of antibody Fc-mediated effector functions in immune defense has been widely reported in various viral infections. These effector functions confer cellular responses through engagement with innate immune cells. The precise mechanism(s) by which immunoglobulin G (IgG) Fc domain and cognate receptors may afford protection are poorly understood, however, in the context of HIV/SHIV infections. Many different in vitro assays have been developed and utilized to measure effector functions, but the extent to which these assays capture distinct antibody activities has not been fully elucidated.ResultsIn this study, six Fc-mediated effector function assays and two biophysical antibody profiling assays were performed on a common set of samples from HIV-1 infected and vaccinated subjects. Biophysical antibody profiles supported robust prediction of diverse IgG effector functions across distinct Fc-mediated effector function assays. While a number of assays showed correlated activities, supervised machine learning models indicated unique antibody features as primary contributing factors to the associated effector functions. Additional experiments established the mechanistic relevance of relationships discovered using this unbiased approach.ConclusionsIn sum, this study provides better resolution on the diversity and complexity of effector function assays, offering a clearer perspective into this family of antibody mechanisms of action to inform future HIV-1 treatment and vaccination strategies.
Highlights
The critical role of antibody Fc-mediated effector functions in immune defense has been widely reported in various viral infections
Purified polyclonal antibodies collected from chronically infected subjects on and off anti-retroviral therapy, elite controllers, and VAX004 HIV-1 recombinant gp120 vaccine and placebo recipients were previously tested in six different immunoglobulin G (IgG) effector function assays conducted by different labs [48]
Given the challenges in achieving high titers of broadly neutralizing antibodies, the discrepancy between antibody quantity and antibody quality have posed special challenges to development of an effective HIV-vaccine. Because both non-human primates (NHP) and human immune correlate studies of experimental vaccines have suggested the importance of antibody effector functions [46, 85,86,87], these functions offer an additional means to restrict infection, thereby motivating interest in defining how different aspects of antibody quality and quantity contribute to diverse activities
Summary
The critical role of antibody Fc-mediated effector functions in immune defense has been widely reported in various viral infections. Increasing evidence from animal models suggests that antibody effector functions play a critical role in protective vaccine-mediated immunity. These activities include antibody-dependent phagocytosis [13], complement-dependent cytotoxicity (CDC) [14], antibody-dependent cellular viral inhibition (ADCVI) [15], and antibody-dependent cellular cytotoxicity (ADCC) [16], among others. Polyfunctional antibody responses—those exhibiting the ability to elicit the anti-viral activities of diverse effector cell subsets, have been reported to correlate with protection in vaccine studies [23]. The most definitive work to date that these correlations may represent mechanisms of protection comes from a passive transfer experiment in which polyfunctional but non-neutralizing antibodies were shown to protect NHP from SIV infection [24]
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