Potent HIV-1 neutralizing monoclonal antibodies have been isolated and are being developed for passive immunotherapy. It is assumed that neutralizing ability in vitro will provide a good indication for anti-viral efficacy in vivo. To what extent antibody-mediated functions associated with Fc region contribute to viral clearance is however unclear. In particular, interactions with Fc- or complement receptors may potentiate neutralization or, under certain condition, potentiate infection. The particular type of receptor involved may have a profound effect on outcome of the interaction of virus-antibody complexes with effector cells. The role of Fc-mediated functions in HIV-1 clearance will be studied in detail by preparing a set of variants of the potent broadly HIV-1 neutralizing antibody IgG1 b12. These variants will have point-mutations introduced into their heavy chain constant domains targeted to specifically knock out selected effector mechanisms. Effects on HIV-1 inactivation by b12 will be studied in vitro and in vivo using primary isolates of HIV-1.