LAUSR

Significance Virus-neutralizing monoclonal antibodies have been tested for the treatment or prevention of HIV-1 infection. Such an antibody can block virus infectivity and mediate killing of virus-infected cells by Fc-mediated effector functions. The relative contributions of these two antibody activities in vivo have not been quantified previously. By quantitatively analyzing results from experiments conducted in HIV-1–infected humanized mice and SHIV-infected rhesus macaques, we have determined that Fc-mediated effector functions contribute about 25–45% to the total antiviral activity of the anti–HIV-1 monoclonal antibodies tested. In combating viral infections, the Fab portion of an antibody could mediate virus neutralization, whereas Fc engagement of Fc-γ receptors (FcγRs) could mediate an array of effector functions. Evidence abounds that effector functions are important in controlling infections by influenza, Ebola, or HIV-1 in animal models. However, the relative contribution of virus neutralization versus effector functions to the overall antiviral activity of an antibody remains unknown. To address this fundamental question in immunology, we utilized our knowledge of HIV-1 dynamics to compare the kinetics of the viral load decline (ΔVL) in infected animals given a wild-type (WT) anti–HIV-1 immunoglobulin G1 (IgG1) versus those given a Fc-Null variant of the same antibody. In three independent experiments in HIV-1–infected humanized mice and one pivotal experiment in simian–human immunodeficiency virus (SHIV)-infected rhesus macaques, an earlier and sharper decline in viral load was consistently detected for the WT antibody. Quantifications of the observed differences indicate that Fc-mediated effector functions accounted for 25–45% of the total antiviral activity in these separate experiments. In this study, Fc-mediated effector functions have been quantified in vivo relative to the contribution of virus neutralization mediated by the Fab.