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

Hoffmann, Magnus A. G. and Bar-On, Yotam and Yang, Zhi and Gristick, Harry B. and Gnanapragasam, Priyanthi N. P. and Vielmetter, Jost and Nussenzweig, Michel C. and Bjorkman, Pamela J. (2020) Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells. Proceedings of the National Academy of Sciences of the United States of America, 117 (31). pp. 18719-18728. ISSN 0027-8424. PMCID PMC7414181. https://resolver.caltech.edu/CaltechAUTHORS:20200720-150827662

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.2010320117DOIArticle
https://www.pnas.org/content/suppl/2020/07/17/2010320117.DCSupplementalPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414181PubMed CentralArticle
ORCID:
AuthorORCID
Hoffmann, Magnus A. G.0000-0003-4923-9568
Bar-On, Yotam0000-0003-4378-707X
Yang, Zhi0000-0001-8680-3784
Gristick, Harry B.0000-0002-1957-2821
Vielmetter, Jost0000-0002-4314-7163
Nussenzweig, Michel C.0000-0003-0592-8564
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2020 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY). Contributed by Pamela J. Bjorkman, June 21, 2020 (sent for review May 27, 2020; reviewed by Nathaniel R. Landau and Roland K. Strong). PNAS first published July 20, 2020. We thank the Caltech Protein Expression Center in the Beckman Institute, Y. E. Lee, and T. Luong for expression of VLPs and proteins; J. R. Keeffe for reagents; M. G. Murphy for help with figures; C. Kieffer and A. P. West for helpful discussion and advice; J. C. C. Lorenzi for primary viral isolates; T. Eisenreich and L. Nogueira for help with hu-mouse experiments; J. A. Pai for bioinformatic analyses; and the NIH AIDS Reagent Program for reagents. Cryo-ET was performed in the Beckman Institute Resource Center for Transmission Electron Microscopy at Caltech. This work was supported by the Bill and Melinda Gates Foundation (Grant OPP1202246) and by a generous gift from Kairos Ventures. Data and Materials Availability: All data associated with this study are available in the main text or SI Appendix. Author contributions: M.A.G.H., Y.B.-O., Z.Y., H.B.G., J.V., M.C.N., and P.J.B. designed research; M.A.G.H., Y.B.-O., Z.Y., H.B.G., and P.N.P.G. performed research; M.A.G.H., Y.B.-O., Z.Y., H.B.G., M.C.N., and P.J.B. analyzed data; and M.A.G.H. and P.J.B. wrote the paper. Reviewers: N.R.L., New York University Langone Medical Center; and R.K.S., Fred Hutchinson Cancer Research Center. The authors declare no competing interest. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2010320117/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
Bill and Melinda Gates FoundationOPP1202246
Kairos VenturesUNSPECIFIED
Subject Keywords:HIV-1; decoy therapeutics; virus-like particles; functional cure
Issue or Number:31
PubMed Central ID:PMC7414181
Record Number:CaltechAUTHORS:20200720-150827662
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200720-150827662
Official Citation:Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells. Magnus A. G. Hoffmann, Yotam Bar-On, Zhi Yang, Harry B. Gristick, Priyanthi N. P. Gnanapragasam, Jost Vielmetter, Michel C. Nussenzweig, Pamela J. Bjorkman. Proceedings of the National Academy of Sciences Aug 2020, 117 (31) 18719-18728; DOI: 10.1073/pnas.2010320117
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104466
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Jul 2020 15:35
Last Modified:24 Aug 2020 16:13

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