The CD4 receptor on host immune cells is the primary receptor for HIV-1 entry and infection. The CD4-binding site (CD4bs) is a highly conserved, conformational, and discontinuous region in the envelope of HIV-1, HIV-2, and also in SIV (9–12). An anti-CD4bs bnAb VRC01 was isolated from a subtype B infected slow-progressor by constructing a resurfaced stabilized core protein, the best antigen designed so far to identify bnAbs against CD4bs region (13). Further, a number of bnAbs of the VRC01 class have been generated, suggesting that the CD4bs region is a prime target for bnAbs with high potency and breadth (14–16). In recent Phase I clinical trials, passive infusion of anti-CD4bs bnAbs 3BNC117 and VRC01 demonstrated reduced viremia in HIV-1-infected donors (17–22), suggesting that bnAbs directed against the CD4bs can serve as potential candidates for immunotherapy and to guide immunogen design.