Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies.
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...
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2019-09-01
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doaj-3844ced64c8c413cb77bd6f0f21b0bcd2021-04-21T17:55:02ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742019-09-01159e100802610.1371/journal.ppat.1008026Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies.Celia C LaBrancheRory HendersonAllen HsuShay BehrensXuejun ChenTongqing ZhouKevin WieheKevin O SaundersS Munir AlamMattia BonsignoriMario J BorgniaQuentin J SattentauAmanda EatonKelli GreeneHongmei GaoHua-Xin LiaoWilton B WilliamsJames PeacockHaili TangLautaro G PerezRobert J EdwardsThomas B KeplerBette T KorberPeter D KwongJohn R MascolaPriyamvada AcharyaBarton F HaynesDavid C MontefioriThe 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.https://doi.org/10.1371/journal.ppat.1008026 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Celia C LaBranche Rory Henderson Allen Hsu Shay Behrens Xuejun Chen Tongqing Zhou Kevin Wiehe Kevin O Saunders S Munir Alam Mattia Bonsignori Mario J Borgnia Quentin J Sattentau Amanda Eaton Kelli Greene Hongmei Gao Hua-Xin Liao Wilton B Williams James Peacock Haili Tang Lautaro G Perez Robert J Edwards Thomas B Kepler Bette T Korber Peter D Kwong John R Mascola Priyamvada Acharya Barton F Haynes David C Montefiori |
spellingShingle |
Celia C LaBranche Rory Henderson Allen Hsu Shay Behrens Xuejun Chen Tongqing Zhou Kevin Wiehe Kevin O Saunders S Munir Alam Mattia Bonsignori Mario J Borgnia Quentin J Sattentau Amanda Eaton Kelli Greene Hongmei Gao Hua-Xin Liao Wilton B Williams James Peacock Haili Tang Lautaro G Perez Robert J Edwards Thomas B Kepler Bette T Korber Peter D Kwong John R Mascola Priyamvada Acharya Barton F Haynes David C Montefiori Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies. PLoS Pathogens |
author_facet |
Celia C LaBranche Rory Henderson Allen Hsu Shay Behrens Xuejun Chen Tongqing Zhou Kevin Wiehe Kevin O Saunders S Munir Alam Mattia Bonsignori Mario J Borgnia Quentin J Sattentau Amanda Eaton Kelli Greene Hongmei Gao Hua-Xin Liao Wilton B Williams James Peacock Haili Tang Lautaro G Perez Robert J Edwards Thomas B Kepler Bette T Korber Peter D Kwong John R Mascola Priyamvada Acharya Barton F Haynes David C Montefiori |
author_sort |
Celia C LaBranche |
title |
Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies. |
title_short |
Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies. |
title_full |
Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies. |
title_fullStr |
Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies. |
title_full_unstemmed |
Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies. |
title_sort |
neutralization-guided design of hiv-1 envelope trimers with high affinity for the unmutated common ancestor of ch235 lineage cd4bs broadly neutralizing antibodies. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2019-09-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.ppat.1008026 |
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