Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancester of CH235 lineage CD4bs broadly neutralizing antibodies

English version

Autoři: Celia C. LaBranche ^aff001; Rory Henderson ^aff002; Allen Hsu ^aff003; Shay Behrens ^aff001; Xuejun Chen ^aff004; Tongqing Zhou ^aff004; Kevin Wiehe ^aff002; Kevin O. Saunders ^aff001; S. Munir Alam ^aff002; Mattia Bonsignori ^aff002; Mario J. Borgnia ^aff003; Quentin J. Sattentau ^aff006; Amanda Eaton ^aff001; Kelli Greene ^aff001; Hongmei Gao ^aff001; Hua-Xin Liao ^aff002; Wilton B. Williams ^aff002; James Peacock ^aff002; Haili Tang ^aff001; Lautaro G. Perez ^aff001; Robert J. Edwards ^aff002; Thomas B. Kepler ^aff007; Bette T. Korber ^aff008; Peter D. Kwong ^aff004; John R. Mascola ^aff004; Priyamvada Acharya ^aff001; Barton F. Haynes ^aff002; David C. Montefiori ^aff001
Působiště autorů: Department of Surgery, Duke University Medical Center, Durham, NC, United States of America ^aff001; Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, United States of America ^aff002; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, United States of America ^aff003; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America ^aff004; Department of Medicine, Duke University Medical Center, Durham, NC, United States of America ^aff005; The Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom ^aff006; Department of Microbiology, Boston University School of Medicine, Boston, MA, United States of America ^aff007; Los Alamos National Laboratory, Theoretical Biology & Biophysics, Los Alamos, NM, United States of America ^aff008
Vyšlo v časopise: Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancester of CH235 lineage CD4bs broadly neutralizing antibodies. PLoS Pathog 15(9): e1008026. doi:10.1371/journal.ppat.1008026
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008026

Souhrn

The CD4 binding site (CD4bs) of the HIV-1 envelope glycoprotein is susceptible to multiple lineages of broadly neutralizing antibodies (bnAbs) that are attractive to elicit with vaccines. The CH235 lineage (VH1-46) of CD4bs bnAbs is particularly attractive because the most mature members neutralize 90% of circulating strains, do not possess long HCDR3 regions, and do not contain insertions and deletions that may be difficult to induce. We used virus neutralization to measure the interaction of CH235 unmutated common ancestor (CH235 UCA) with functional Env trimers on infectious virions to guide immunogen design for this bnAb lineage. Two Env mutations were identified, one in loop D (N279K) and another in V5 (G458Y), that acted synergistically to render autologous CH505 transmitted/founder virus susceptible to neutralization by CH235 UCA. Man₅-enriched N-glycans provided additional synergy for neutralization. CH235 UCA bound with nanomolar affinity to corresponding soluble native-like Env trimers as candidate immunogens. A cryo-EM structure of CH235 UCA bound to Man₅-enriched CH505.N279K.G458Y.SOSIP.664 revealed interactions of the antibody light chain complementarity determining region 3 (CDR L3) with the engineered Env loops D and V5. These results demonstrate that virus neutralization can directly inform vaccine design and suggest a germline targeting and reverse engineering strategy to initiate and mature the CH235 bnAb lineage.

Klíčová slova:

Biology and life sciences – Microbiology – Medical microbiology – Microbial pathogens – Viral pathogens – Immunodeficiency viruses – HIV – HIV-1 – Retroviruses – Lentivirus – Organisms – Viruses – RNA viruses – Physiology – Antigens – Antibodies – Biochemistry – Proteins – Immune system proteins – Genetics – Mutation – Point mutation – Molecular biology – Molecular biology techniques – Transfection – Medicine and health sciences – Pathology and laboratory medicine – Pathogens – Immune physiology – Immunology – Health care – Research and analysis methods – Microscopy – Electron microscopy – Electron cryo-microscopy – Biological cultures – Cell lines – 293T cells

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