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A role for antibody-dependent cellular cytotoxicity (ADCC) in controlling initial development of HIV-1 infection is supported by a growing number of studies. 2F5, a broadly HIV-1-neutralizing IgG specific for HIV-1 envelope gp41, has been extensively studied in vitro and in vivo for its neutralizing and transcytosis-blocking activities. In the present paper, we have studied the in vitro ADCC potential of 2F5.We have developed an ADCC model based on either monocytic cell line THP1 or monocytes, both FcγRI+ FcγRIII- as effector cells, and natural killer resistant-CEM (NKr-CEM) either coated with HIV envelope subunit, or stably expressing an X4 tropic HIV-1 envelope as target cells. Finally, in order to better simulate the in vivo situation, we used R5-tropic JR-CSF HIV-1-infected NKr-CEM as targets.ADCC was monitored using a fluorescently based, nonradioactive, easy to use assay.2F5 triggered ADCC of HIV-1 envelope subunit coated cells. Remarkably, 2F5 at ng/ml concentration elicited ADCC of both X4-tropic HIV-1 envelope-expressing cells, and R5-HIV-infected cells. ADCC relied on binding to the FcγRI on effector cell and was abolished by preincubation of 2F5 with its cognate epitope ELDKWA.The capacity of the broadly neutralizing 2F5 to elicit ADCC, and thereby linking adaptive and innate immunity, expands its prophylactic potential. Raising antibodies to the membrane proximal region of HIV-1 envelope with similar ADCC properties, in addition to neutralization, should be taken into account in HIV-1 vaccine design.