Broadly neutralizing antibody recognition of diverse HIV envelopes modulates effector function

Abstract

While neutralization of free virus is essential for protection against HIV transmission, the fragment crystallizable (Fc) region mediated functions of broadly neutralizing antibodies (bNAbs) have also been shown to be critical for protection in animal models, namely antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Multiple sites of vulnerability on the viral envelope (Env) have been described that serve as targets for bNAb binding to neutralize HIV. The diverse locations of these sites on Env suggest that they may result in differential accessibility of innate effector cells to bound bNAb. Effector cells utilize different FcRs to engage the Fc-region of an antibody to drive effector functions. As such, the accessibility of antibody Fc-regions when bound to a specific epitope may allow an antibody to effectively drive one effector function while a different epitope may be a more ideal target to mediate another. Here, we determine how binding to five different sites of vulnerability influences the ability of innate immune cells to mediate antibody-dependent effector functions against Env-expressing target cells. Our results show that bNAb-mediated effector functions are dependent upon bNAb binding site, with V1V2-directed bNAbs engaging monocytes to efficiently drive ADCP while MPER and Interface-directed antibodies potently mediate ADCC. We found that CD4bs and V3-directed antibodies are effective mediators of both functions. Additionally, we find that the potency of a given antibody to mediate effector functions across diverse envelopes is driven by differential binding of FcRs, suggesting that antibody binding to its epitope can impact binding of innate cell receptors. Collectively, this work helps elucidate optimal vaccine targets capable of maximal effector functions, thereby informing future prevention strategies against HIV.