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

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Item Type:Article
Title:Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies
Creators Name:LaBranche, C.C. and Henderson, R. and Hsu, A. and Behrens, S. and Chen, X. and Zhou, T. and Wiehe, K. and Saunders, K.O. and Alam, S.M. and Bonsignori, M. and Borgnia, M.J. and Sattentau, Q.J. and Eaton, A. and Greene, K. and Gao, H. and Liao, H.X. and Williams, W.B. and Peacock, J. and Tang, H. and Perez, L.G. and Edwards, R.J. and Kepler, T.B. and Korber, B.T. and Kwong, P.D. and Mascola, J.R. and Acharya, P. and Haynes, B.F. and Montefiori, D.C.
Abstract: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.
Keywords:AIDS Vaccines, Amino Acid Substitution, Antibody Affinity, Binding Sites, Broadly Neutralizing Antibodies, CD4 Antigens, Drug Design, Epitopes, HEK293 Cells, HIV Antibodies, HIV Infections, HIV-1, Host Microbial Interactions, Human Immunodeficiency Virus env Gene Products, Molecular Models, Protein Engineering, Protein Multimerization, Quaternary Protein Structure, Site-Directed Mutagenesis
Source:PLoS Pathogens
Publisher:Public Library of Science
Page Range:e1008026
Date:17 September 2019
Additional Information:Erratum in: PLoS Pathog 15(12): e1008200.
Official Publication:https://doi.org/10.1371/journal.ppat.1008026
PubMed:View item in PubMed

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