Detailed studies of the broadly neutralizing antibodies (bNAbs) that underlie the best available examples of the humoral immune response to HIV are providing important information for the development of therapies and prophylaxis for HIV-1 infection. Here, we report a CD4-binding site (CD4bs) antibody, named N6, that potently neutralized 98% of HIV-1 isolates, including 16 of 20 that were resistant to other members of its class. N6 evolved a mode of recognition such that its binding was not impacted by the loss of individual contacts across the immunoglobulin heavy chain. In addition, structural analysis revealed that the orientation of N6 permitted it to avoid steric clashes with glycans, which is a common mechanism of resistance. Thus, an HIV-1-specific bNAb can achieve potent, near-pan neutralization of HIV-1, making it an attractive candidate for use in therapy and prophylaxis.

Passive immunotherapy against HIV-1 will most likely require broadly neutralizing antibodies (bnAbs) with maximum breadth and potency to ensure therapeutic efficacy. Recently, the novel CD4 binding site antibody N6 demonstrated extraordinary neutralization breadth and potency against large panels of cross-clade pseudoviruses. We evaluated the in vivo antiviral activity of N6-LS, alone or in combination with the established V3-glycan antibody PGT121, in chronically simian-human immunodeficiency virus (SHIV)-SF162P3-infected macaques. A single dose of N6-LS suppressed plasma viral loads in 4 out of 5 animals at day 7, while the combination of both antibodies suppressed all animals. The combination of both antibodies had no additive antiviral effect compared to a single dose of PGT121, potentially reflecting the nearly 10-fold-higher potency of PGT121 against this SHIV. Viral rebound occurred in the majority of suppressed animals and was linked to declining plasma bnAb levels over time. In addition to the effect on plasma viremia, bnAb administration resulted in significantly reduced proviral DNA levels in PBMCs after 2 weeks and in lymph nodes after 10 weeks. Autologous neutralizing antibody (nAb) responses and CD8+ T-cell responses were not significantly enhanced in the bnAb-treated animals compared to control animals, arguing against their contribution to the viral effects observed. These results confirm the robust antiviral activity of N6-LS in vivo, supporting the further clinical development of this antibody.IMPORTANCE Monocloncal antibodies (MAbs) are being considered for passive immunotherapy of HIV-1 infection. A critical requirement for such strategies is the identification of MAbs that recognize the diversity of variants within circulating but also reservoir viruses, and MAb combinations might be needed to achieve this goal. This study evaluates the novel bnAb N6-LS alone or in combination with the bnAb PGT121, in rhesus macaques that were chronically infected with SHIV. The results demonstrate that N6-LS potently suppressed plasma viral loads in the majority of animals but that the combination with PGT121 was not superior to PGT121 alone in delaying time to viral rebound or reducing peripheral blood mononuclear cell (PBMC) or lymph node proviral DNA levels. The occurrence of viral escape variants in an N6-LS-monotreated animal, however, argues for the need to maximize breadth and antiviral efficacy by combining bnAbs for therapeutic indications.