Recent SHIV-challenge studies using conformationally constrained immunogens suggest a correlation between protective immunity and the presence of antibodies specific for epitopes that are exposed selectively during viral entry (DeVico, et.al., PNAS, 104:17477-82, 2007). We recently established methods to census memory B cells and isolate monoclonal antibodies (mAbs) from HIV infected people (Guan, et. al. PNAS, 106:3952-7.2009) to directly test this correlation by passive immunization. To this end, we have identified three groups of mAbs specific for gp120 epitopes whose exposures are increased by the binding of CD4 or strictly dependent upon it. Group I mAbs bind approximately 10-fold better to gp120-CD4 complexes than to gp120. Group II mAbs bind 100 to 1000-fold better to gp120-CD4 complexes than to gp120. Group III mAbs only bind to gp120-CD4 complexes with no measurable binding to free gp120. Examples of Group I and Group II mAbs are known (i.e., mAb A32 and mAb 17b, respectively); however, Group III mAbs have not been observed in humans. One Group III mAb, N12-I15, isolated from an HIV-1 controller exhibited unusual properties in functional studies. It is non-neutralizing in the TZM-bl assay but strongly potent in antibody dependent cell mediated cytotoxicity assays (ADCC), which is a measure of Fc-mediated effector function. This mAb potently arms effector cells to kill CD4+ CCR5+ target cells that are sensitized with monomeric gp120, trimeric gp140, or an R5 pseudovirus. The strict dependence of epitope exposure on CD4 binding for this mAb and its ability to strongly facilitate killing of target cells sensitized with trimeric gp140 or an R5 pseudovirus, suggests that it recognizes a novel epitope that is highly exposed during viral entry and that this epitope might be a new target for protective immune responses elicited by vaccination.