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
Magnus A G HoffmannPamela J Bjorkman

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 con...Continue Reading

References

Sep 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·E S DaarD D Ho
Jul 1, 1993·AIDS Research and Human Retroviruses·P J Klasse, J A McKeating
Jul 25, 2007·Retrovirology·Anna LaurénEva Maria Fenyö
Dec 10, 2008·Cell Host & Microbe·Lars-Anders CarlsonHans-Georg Kräusslich
Jun 5, 2010·PLoS Pathogens·Joshua S Klein, Pamela J Bjorkman
Jan 8, 2011·Annual Review of Pharmacology and Toxicology·Shailesh K Choudhary, David M Margolis
Jul 19, 2011·Journal of Molecular Biology·Nancy L GoicocheaBogdan Dragnea
Jan 10, 2012·Cold Spring Harbor Perspectives in Medicine·Robert F Siliciano, Warner C Greene
Oct 30, 2012·Nature·Florian KleinMichel C Nussenzweig
Apr 2, 2013·Lancet·Christine KatlamaRafick P Sekaly
Jun 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·Anthony P WestPamela J Bjorkman
Jan 31, 2015·Cell·Rachel P GalimidiPamela J Bjorkman
Feb 25, 2015·Nature·Matthew R GardnerMichael Farzan
Mar 13, 2015·The Journal of General Virology·Hanna DrejaÁine McKnight
Apr 2, 2015·Proceedings of the National Academy of Sciences of the United States of America·Kyung-Ho RohMark M Davis
Apr 14, 2015·Virology·Stephen C Harrison
May 5, 2016·Methods in Molecular Biology·Yasuyuki SaitoMarkus G Manz
Jun 2, 2016·Proceedings of the National Academy of Sciences of the United States of America·Hui LiGeorge M Shaw
Nov 23, 2016·Proceedings of the National Academy of Sciences of the United States of America·Julio C C LorenziMichel C Nussenzweig
Jan 17, 2017·Nature Medicine·Marina CaskeyFlorian Klein
Apr 20, 2017·Current Opinion in HIV and AIDS·Matthew R Gardner, Michael Farzan
May 30, 2017·Molecular Therapy : the Journal of the American Society of Gene Therapy·Conrad A VinkSteven J Howe
Jun 19, 2017·Molecular Therapy. Nucleic Acids·Alexander Falkenhagen, Sadhna Joshi
Dec 28, 2017·PLoS Pathogens·Johannes S GachDonald N Forthal
May 31, 2018·Current Opinion in HIV and AIDS·Timothée Bruel, Olivier Schwartz
Aug 4, 2018·The Journal of Experimental Medicine·Yehuda Z CohenMichel C Nussenzweig

❮ Previous
Next ❯

Citations

Mar 17, 2021·Molecular Therapy. Methods & Clinical Development·Magnus A G HoffmannPamela J Bjorkman
Jun 18, 2021·Nature Communications·Edurne RujasJean-Philippe Julien
Jul 22, 2021·Journal of Clinical Microbiology·Anton M SholukhLawrence Corey

❮ Previous
Next ❯

Methods Mentioned

BETA
ELISAs
size exclusion chromatography
ELISA
electrophoresis
biosensor
chip
flow cytometry
Assay

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.