LAUSR

Increasingly, antibodies are being used to treat and prevent viral infections. In the context of HIV, efficacy is primarily attributed to dose-dependent neutralization potency and to a lesser extent Fc-mediated effector functions. It remains unclear whether augmenting effector functions of broadly neutralizing antibodies (bNAbs) may improve their clinical potential. Here, we use bNAb 10E8v4 targeting the membrane external proximal region (MPER) to examine the role of antibody-mediated effector and complement (C’) activity when administered prophylactically against SHIV challenge in rhesus macaques. With sub-protective dosing, we find a 78–88% reduction in post-acute viremia that is associated with 10E8v4-mediated phagocytosis acting at the time of challenge. Neither plasma nor tissue viremic outcomes in vivo is improved with an Fc-modified variant of 10E8v4 enhanced for C’ functions as determined in vitro. These results suggest that effector functions inherent to unmodified 10E8v4 contribute to efficacy against SHIV SF162P3 in the absence of plasma neutralizing titers, while C’ functions are dispensable in this setting, informing design of bNAb modifications for improving protective efficacy. While antibodies neutralize HIV via Fab recognition of viral surface antigens, antibody Fc domains mediate effector functions, including antibody-dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC), and complement (C') activity. Here, Spencer et al. modify bNAb 10E8v4 to enhance C'-mediated potency in SHIV challenged rhesus macaques to probe its function in protection, showing that in the absence of neutralization, enhancing C' activities in vitro adds no value toward reducing viremia in either blood or tissue.