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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.

Publication ,  Journal Article
LaBranche, CC; Henderson, R; Hsu, A; Behrens, S; Chen, X; Zhou, T; Wiehe, K; Saunders, KO; Alam, SM; Bonsignori, M; Borgnia, MJ; Sattentau, QJ ...
Published in: PLoS Pathog
September 2019

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.

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Published In

PLoS Pathog

DOI

EISSN

1553-7374

Publication Date

September 2019

Volume

15

Issue

9

Start / End Page

e1008026

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Virology
  • Protein Structure, Quaternary
  • Protein Multimerization
  • Protein Engineering
  • Mutagenesis, Site-Directed
  • Models, Molecular
  • Humans
  • Host Microbial Interactions
  • HIV-1
 

Citation

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MLA
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LaBranche, C. C., Henderson, R., Hsu, A., Behrens, S., Chen, X., Zhou, T., … Montefiori, D. C. (2019). Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies. PLoS Pathog, 15(9), e1008026. https://doi.org/10.1371/journal.ppat.1008026
LaBranche, Celia C., Rory Henderson, Allen Hsu, Shay Behrens, Xuejun Chen, Tongqing Zhou, Kevin Wiehe, et al. “Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies.PLoS Pathog 15, no. 9 (September 2019): e1008026. https://doi.org/10.1371/journal.ppat.1008026.
LaBranche, Celia C., et al. “Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies.PLoS Pathog, vol. 15, no. 9, Sept. 2019, p. e1008026. Pubmed, doi:10.1371/journal.ppat.1008026.
LaBranche CC, Henderson R, Hsu A, Behrens S, Chen X, Zhou T, Wiehe K, Saunders KO, Alam SM, Bonsignori M, Borgnia MJ, Sattentau QJ, Eaton A, Greene K, Gao H, Liao H-X, Williams WB, Peacock J, Tang H, Perez LG, Edwards RJ, Kepler TB, Korber BT, Kwong PD, Mascola JR, Acharya P, Haynes BF, Montefiori DC. Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies. PLoS Pathog. 2019 Sep;15(9):e1008026.

Published In

PLoS Pathog

DOI

EISSN

1553-7374

Publication Date

September 2019

Volume

15

Issue

9

Start / End Page

e1008026

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Virology
  • Protein Structure, Quaternary
  • Protein Multimerization
  • Protein Engineering
  • Mutagenesis, Site-Directed
  • Models, Molecular
  • Humans
  • Host Microbial Interactions
  • HIV-1