Cargando…

Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells

CD4-based decoy approaches against HIV-1 are attractive options for long-term viral control, but initial designs, including soluble CD4 (sCD4) and CD4-Ig, were ineffective. To evaluate a therapeutic that more accurately mimics HIV-1 target cells compared with monomeric sCD4 and dimeric CD4-Ig, we ge...

Descripción completa

Detalles Bibliográficos
Autores principales: Hoffmann, Magnus A. G., Bar-On, Yotam, Yang, Zhi, Gristick, Harry B., Gnanapragasam, Priyanthi N. P., Vielmetter, Jost, Nussenzweig, Michel C., Bjorkman, Pamela J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414181/
https://www.ncbi.nlm.nih.gov/pubmed/32690692
http://dx.doi.org/10.1073/pnas.2010320117
_version_ 1783568923689484288
author Hoffmann, Magnus A. G.
Bar-On, Yotam
Yang, Zhi
Gristick, Harry B.
Gnanapragasam, Priyanthi N. P.
Vielmetter, Jost
Nussenzweig, Michel C.
Bjorkman, Pamela J.
author_facet Hoffmann, Magnus A. G.
Bar-On, Yotam
Yang, Zhi
Gristick, Harry B.
Gnanapragasam, Priyanthi N. P.
Vielmetter, Jost
Nussenzweig, Michel C.
Bjorkman, Pamela J.
author_sort Hoffmann, Magnus A. G.
collection PubMed
description CD4-based decoy approaches against HIV-1 are attractive options for long-term viral control, but initial designs, including soluble CD4 (sCD4) and CD4-Ig, were ineffective. To evaluate a therapeutic that more accurately mimics HIV-1 target cells compared with monomeric sCD4 and dimeric CD4-Ig, we generated virus-like nanoparticles that present clusters of membrane-associated CD4 (CD4-VLPs) to permit high-avidity binding of trimeric HIV-1 envelope spikes. In neutralization assays, CD4-VLPs were >12,000-fold more potent than sCD4 and CD4-Ig and >100-fold more potent than the broadly neutralizing antibody (bNAb) 3BNC117, with >12,000-fold improvements against strains poorly neutralized by 3BNC117. CD4-VLPs also neutralized patient-derived viral isolates that were resistant to 3BNC117 and other bNAbs. Intraperitoneal injections of CD4-CCR5-VLP produced only subneutralizing plasma concentrations in HIV-1–infected humanized mice but elicited CD4-binding site mutations that reduced viral fitness. All mutant viruses showed reduced sensitivity to sCD4 and CD4-Ig but remained sensitive to neutralization by CD4-VLPs in vitro. In vitro evolution studies demonstrated that CD4-VLPs effectively controlled HIV-1 replication at neutralizing concentrations, and viral escape was not observed. Moreover, CD4-VLPs potently neutralized viral swarms that were completely resistant to CD4-Ig, suggesting that escape pathways that confer resistance against conventional CD4-based inhibitors are ineffective against CD4-VLPs. These findings suggest that therapeutics that mimic HIV-1 target cells could prevent viral escape by exposing a universal vulnerability of HIV-1: the requirement to bind CD4 on a target cell. We propose that therapeutic and delivery strategies that ensure durable bioavailability need to be developed to translate this concept into a clinically feasible functional cure therapy.
format Online
Article
Text
id pubmed-7414181
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-74141812020-08-21 Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells Hoffmann, Magnus A. G. Bar-On, Yotam Yang, Zhi Gristick, Harry B. Gnanapragasam, Priyanthi N. P. Vielmetter, Jost Nussenzweig, Michel C. Bjorkman, Pamela J. Proc Natl Acad Sci U S A Biological Sciences CD4-based decoy approaches against HIV-1 are attractive options for long-term viral control, but initial designs, including soluble CD4 (sCD4) and CD4-Ig, were ineffective. To evaluate a therapeutic that more accurately mimics HIV-1 target cells compared with monomeric sCD4 and dimeric CD4-Ig, we generated virus-like nanoparticles that present clusters of membrane-associated CD4 (CD4-VLPs) to permit high-avidity binding of trimeric HIV-1 envelope spikes. In neutralization assays, CD4-VLPs were >12,000-fold more potent than sCD4 and CD4-Ig and >100-fold more potent than the broadly neutralizing antibody (bNAb) 3BNC117, with >12,000-fold improvements against strains poorly neutralized by 3BNC117. CD4-VLPs also neutralized patient-derived viral isolates that were resistant to 3BNC117 and other bNAbs. Intraperitoneal injections of CD4-CCR5-VLP produced only subneutralizing plasma concentrations in HIV-1–infected humanized mice but elicited CD4-binding site mutations that reduced viral fitness. All mutant viruses showed reduced sensitivity to sCD4 and CD4-Ig but remained sensitive to neutralization by CD4-VLPs in vitro. In vitro evolution studies demonstrated that CD4-VLPs effectively controlled HIV-1 replication at neutralizing concentrations, and viral escape was not observed. Moreover, CD4-VLPs potently neutralized viral swarms that were completely resistant to CD4-Ig, suggesting that escape pathways that confer resistance against conventional CD4-based inhibitors are ineffective against CD4-VLPs. These findings suggest that therapeutics that mimic HIV-1 target cells could prevent viral escape by exposing a universal vulnerability of HIV-1: the requirement to bind CD4 on a target cell. We propose that therapeutic and delivery strategies that ensure durable bioavailability need to be developed to translate this concept into a clinically feasible functional cure therapy. National Academy of Sciences 2020-08-04 2020-07-20 /pmc/articles/PMC7414181/ /pubmed/32690692 http://dx.doi.org/10.1073/pnas.2010320117 Text en Copyright © 2020 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Hoffmann, Magnus A. G.
Bar-On, Yotam
Yang, Zhi
Gristick, Harry B.
Gnanapragasam, Priyanthi N. P.
Vielmetter, Jost
Nussenzweig, Michel C.
Bjorkman, Pamela J.
Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells
title Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells
title_full Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells
title_fullStr Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells
title_full_unstemmed Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells
title_short Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells
title_sort nanoparticles presenting clusters of cd4 expose a universal vulnerability of hiv-1 by mimicking target cells
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414181/
https://www.ncbi.nlm.nih.gov/pubmed/32690692
http://dx.doi.org/10.1073/pnas.2010320117
work_keys_str_mv AT hoffmannmagnusag nanoparticlespresentingclustersofcd4exposeauniversalvulnerabilityofhiv1bymimickingtargetcells
AT baronyotam nanoparticlespresentingclustersofcd4exposeauniversalvulnerabilityofhiv1bymimickingtargetcells
AT yangzhi nanoparticlespresentingclustersofcd4exposeauniversalvulnerabilityofhiv1bymimickingtargetcells
AT gristickharryb nanoparticlespresentingclustersofcd4exposeauniversalvulnerabilityofhiv1bymimickingtargetcells
AT gnanapragasampriyanthinp nanoparticlespresentingclustersofcd4exposeauniversalvulnerabilityofhiv1bymimickingtargetcells
AT vielmetterjost nanoparticlespresentingclustersofcd4exposeauniversalvulnerabilityofhiv1bymimickingtargetcells
AT nussenzweigmichelc nanoparticlespresentingclustersofcd4exposeauniversalvulnerabilityofhiv1bymimickingtargetcells
AT bjorkmanpamelaj nanoparticlespresentingclustersofcd4exposeauniversalvulnerabilityofhiv1bymimickingtargetcells