The broadly neutralizing HIV-1 IgG 2F5 elicits gp41-specific antibody-dependent cell cytotoxicity in a FcγRI-dependent manner

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Objective: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.Design: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.Methods:ADCC was monitored using a fluorescently based, nonradioactive, easy to use assay.Results: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.Conclusion: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.

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