Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody
| Autor: | Udo Holtick, Henning Gruell, Markus Valter, Philipp Schommers, Adam S. Dingens, Harry B. Gristick, Christopher O. Barnes, Clara Lehmann, Daniela Weiland, Gerd Fätkenheuer, Michael S. Seaman, Jörg J. Vehreschild, Pamela J. Bjorkman, Christoph Kreer, Kanika Vanshylla, Rogier W. Sanders, Florian Klein, Till Schoofs, Oliver A. Cornely, Jesse D. Bloom, Maike Schlotz, Marit J. van Gils, Morgan E. Abernathy, My-Kim Tran, Christof Scheid |
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| Přispěvatelé: | Medical Microbiology and Infection Prevention, AII - Infectious diseases |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
medicine.medical_treatment Human immunodeficiency virus (HIV) HIV Infections HIV Antibodies medicine.disease_cause Cohort Studies Epitopes Mice 0302 clinical medicine deep mutational scanning Mice Inbred NOD Neutralizing antibody chemistry.chemical_classification 0303 health sciences biology cryogenic electron microscopy env Gene Products Human Immunodeficiency Virus HIV-1 escape restriction Antibodies Monoclonal virus diseases Middle Aged escape mutations 3. Good health humanized mice CD4 Antigens Heterografts Female immunotherapy Antibody Protein Binding Viremia CHO Cells Article General Biochemistry Genetics and Molecular Biology CD4 binding site 03 medical and health sciences Cricetulus Antigen medicine Animals Humans ddc:610 Binding site 030304 developmental biology Binding Sites broadly neutralizing antibodies Immunotherapy medicine.disease Virology HEK293 Cells chemistry Mutation biology.protein HIV-1 mutational antigenic profiling Glycoprotein 030217 neurology & neurosurgery |
| Zdroj: | Cell, 180(3), 471-489.e22. Cell Press Cell |
| ISSN: | 0092-8674 |
| Popis: | Summary 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. Graphical Abstract Highlights • 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. |
| Databáze: | OpenAIRE |
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