Enhancing HIV-1 neutralization by increasing the local concentration of MPER directed bnAbs

Broadly neutralizing antibodies (bnAbs) against the membrane-proximal external region (MPER) of the gp41 component of the HIV-1 envelope (Env) are characterized by long hydrophobic heavy-chain complementarity-determining regions (HCDR3s) that interact with MPER and some viral membrane lipids, to achieve increased local concentrations. Here, we show that increasing the local concentration of MPER-directed bnAbs at the cell surface via binding to the high affinity Fc receptor (FcγRI) potentiates their ability to prevent viral entry in a manner analogous to the previously reported observation whereby the lipid binding activity of MPER bnAbs increases their concentration at the viral surface membrane. However, binding of MPER-directed bnAb 10E8 to FcγRI abolishes the neutralization synergy that is seen with the N-heptad repeat (NHR)-targeting antibody D5_AR and NHR-targeting small molecule enfuvirtide (T20), possibly due to decreased accessibility of the NHR in the FcγRI-10E8-MPER complex. Taken together, our results suggest that lipid-binding activity and FcγRI-mediated potentiation function in concert to improve the potency of MPER-directed bnAbs by increasing their local concentration near the site of viral fusion. Therefore, lipid-binding may not be a strict requirement for potent neutralization by MPER-targeting bnAbs, as alternative methods can achieve similar increase in local concentration while avoiding potential liabilities associated with immunologic host tolerance.