Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

• Published in: Cell 2020-02, Vol.180 (3), p.471-489.e22
• Main Authors: Schommers, Philipp, Gruell, Henning, Abernathy, Morgan E., Tran, My-Kim, Dingens, Adam S., Gristick, Harry B., Barnes, Christopher O., Schoofs, Till, Schlotz, Maike, Vanshylla, Kanika, Kreer, Christoph, Weiland, Daniela, Holtick, Udo, Scheid, Christof, Valter, Markus M., van Gils, Marit J., Sanders, Rogier W., Vehreschild, Jörg J., Cornely, Oliver A., Lehmann, Clara, Fätkenheuer, Gerd, Seaman, Michael S., Bloom, Jesse D., Bjorkman, Pamela J., Klein, Florian
• Format: Article
• Language: English
• Subjects: broadly neutralizing antibodies; CD4 binding site; cryogenic electron microscopy; deep mutational scanning; escape mutations; HIV-1; HIV-1 escape restriction; humanized mice; immunotherapy; mutational antigenic profiling
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.01.010

Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new VH1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 μg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505SOSIP.664 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection. [Display omitted] •Identification of 1-18, a highly broad and potent VH1-46-derived CD4bs antibody•2.5-Å cryo-EM structure of 1-18-Env complex reveals inter-protomer contacts•1-18 overcomes VRC01-class resistance and restricts development of HIV-1 escape•Monotherapy with 1-18 maintains viral suppression in HIV-1YU2-infected humanized mice Broadly neutralizing antibodies targeting the HIV-1 envelope protein are a promising option for prevention and treatment of HIV-1 infection. However, development of viral resistance can limit clinical efficacy. Schommers et al. identify a highly broad and potent antibody that targets the CD4 binding site of HIV-1. Compared with other potent CD4 binding site antibodies, it restricts the development of viral escape and effectively suppresses HIV-1 in vivo.