Evidence map›Paper›PMID 27470515›Full record

ArticleArteriosclerosis, thrombosis, and vascular biology2016

Interaction Between HIV-1 Nef and Calnexin: From Modeling to Small Molecule Inhibitors Reversing HIV-Induced Lipid Accumulation.

Ruth Hunegnaw, Marina Vassylyeva, Larisa Dubrovsky, Tatiana Pushkarsky, Dmitri Sviridov, Anastasia A Anashkina, Aykut Üren, Beda Brichacek, Dmitry G Vassylyev, Alexei A Adzhubei and 1 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Arteriosclerosis, thrombosis, and vascular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.

0numbers the graph read from it
0cells of the map it votes in
17citing papers in PubMed
1.3field-weighted citation impact, top 21% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

17 citing papers in PubMed, 26 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
  4. Article
  5. Neuro-HIV-New insights into pathogenesis and emerging therapeutic targets.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2023
    Article
  6. Review
  7. Review
  8. Article
  9. The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease.International journal of molecular sciences · 2021
    Review
  10. Article
  11. Review
  12. Tetrapeptide Ac-HAEE-NHInternational journal of molecular sciences · 2020
    Article
  13. Review
  14. Article
  15. Reporting Sex and Sex Differences in Preclinical Studies.Arteriosclerosis, thrombosis, and vascular biology · 2018
    Article
  16. Article
  17. Efficient, ultra-high-affinity chromatography in a one-step purification of complex proteins.Proceedings of the National Academy of Sciences of the United States of America · 2017
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 3 institutions in 3 countries.

Ruth HunegnawFrom the George Washington University School of Medicine and Health Sciences, Washington, DC (R.H., L.D., T.P., B.B., A.A.A., M.B.); University of Alabama School of Medicine and Dentistry, Birmingham, (M.V., D.V.); Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); Engelhardt Institute of Molecular Biology RAS, Moscow, Russia (A.A. Anashkina, A.A. Adzhubei); and Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC (A.Ü).
Marina VassylyevaFrom the George Washington University School of Medicine and Health Sciences, Washington, DC (R.H., L.D., T.P., B.B., A.A.A., M.B.); University of Alabama School of Medicine and Dentistry, Birmingham, (M.V., D.V.); Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); Engelhardt Institute of Molecular Biology RAS, Moscow, Russia (A.A. Anashkina, A.A. Adzhubei); and Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC (A.Ü).
Larisa DubrovskyFrom the George Washington University School of Medicine and Health Sciences, Washington, DC (R.H., L.D., T.P., B.B., A.A.A., M.B.); University of Alabama School of Medicine and Dentistry, Birmingham, (M.V., D.V.); Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); Engelhardt Institute of Molecular Biology RAS, Moscow, Russia (A.A. Anashkina, A.A. Adzhubei); and Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC (A.Ü).
Tatiana PushkarskyFrom the George Washington University School of Medicine and Health Sciences, Washington, DC (R.H., L.D., T.P., B.B., A.A.A., M.B.); University of Alabama School of Medicine and Dentistry, Birmingham, (M.V., D.V.); Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); Engelhardt Institute of Molecular Biology RAS, Moscow, Russia (A.A. Anashkina, A.A. Adzhubei); and Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC (A.Ü).
Dmitri SviridovFrom the George Washington University School of Medicine and Health Sciences, Washington, DC (R.H., L.D., T.P., B.B., A.A.A., M.B.); University of Alabama School of Medicine and Dentistry, Birmingham, (M.V., D.V.); Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); Engelhardt Institute of Molecular Biology RAS, Moscow, Russia (A.A. Anashkina, A.A. Adzhubei); and Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC (A.Ü).
Anastasia A AnashkinaFrom the George Washington University School of Medicine and Health Sciences, Washington, DC (R.H., L.D., T.P., B.B., A.A.A., M.B.); University of Alabama School of Medicine and Dentistry, Birmingham, (M.V., D.V.); Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); Engelhardt Institute of Molecular Biology RAS, Moscow, Russia (A.A. Anashkina, A.A. Adzhubei); and Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC (A.Ü).
Aykut ÜrenFrom the George Washington University School of Medicine and Health Sciences, Washington, DC (R.H., L.D., T.P., B.B., A.A.A., M.B.); University of Alabama School of Medicine and Dentistry, Birmingham, (M.V., D.V.); Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); Engelhardt Institute of Molecular Biology RAS, Moscow, Russia (A.A. Anashkina, A.A. Adzhubei); and Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC (A.Ü).
Beda BrichacekFrom the George Washington University School of Medicine and Health Sciences, Washington, DC (R.H., L.D., T.P., B.B., A.A.A., M.B.); University of Alabama School of Medicine and Dentistry, Birmingham, (M.V., D.V.); Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); Engelhardt Institute of Molecular Biology RAS, Moscow, Russia (A.A. Anashkina, A.A. Adzhubei); and Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC (A.Ü).
Dmitry G VassylyevFrom the George Washington University School of Medicine and Health Sciences, Washington, DC (R.H., L.D., T.P., B.B., A.A.A., M.B.); University of Alabama School of Medicine and Dentistry, Birmingham, (M.V., D.V.); Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); Engelhardt Institute of Molecular Biology RAS, Moscow, Russia (A.A. Anashkina, A.A. Adzhubei); and Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC (A.Ü).
Alexei A AdzhubeiFrom the George Washington University School of Medicine and Health Sciences, Washington, DC (R.H., L.D., T.P., B.B., A.A.A., M.B.); University of Alabama School of Medicine and Dentistry, Birmingham, (M.V., D.V.); Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); Engelhardt Institute of Molecular Biology RAS, Moscow, Russia (A.A. Anashkina, A.A. Adzhubei); and Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC (A.Ü). mbukrins@gwu.edu alexei.adzhubei@eimb.ru.
Michael BukrinskyFrom the George Washington University School of Medicine and Health Sciences, Washington, DC (R.H., L.D., T.P., B.B., A.A.A., M.B.); University of Alabama School of Medicine and Dentistry, Birmingham, (M.V., D.V.); Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); Engelhardt Institute of Molecular Biology RAS, Moscow, Russia (A.A. Anashkina, A.A. Adzhubei); and Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC (A.Ü). mbukrins@gwu.edu alexei.adzhubei@eimb.ru.
Engelhardt Institute of Molecular Biology · RUUniversity of Alabama · USBaker Heart and Diabetes Institute · AU

Funding

Tissue Culture Shared ResourceP30CA051008 · NCI · GEORGETOWN UNIVERSITY · PI STEPHEN W BYERS · 1990 to 2026
$71.5M
SWG 2: Cure Research Scientific Working GroupP30AI117970 · NIAID · GEORGE WASHINGTON UNIVERSITY · PI Italo Mocchetti · 2015 to 2026
$29.6M
HIV Disease and Impairement of High Density Lipoprotein MetabolismR01HL101274 · NHLBI · GEORGE WASHINGTON UNIVERSITY · PI BUKRINSKY, MICHAEL ILYA, FITZGERALD, MICHAEL LEO · 2010 to 2015
$4.0M
Mechanisms of virus-induced impairment of reverse cholesterol transportR01HL093818 · NHLBI · GEORGE WASHINGTON UNIVERSITY · PI BUKRINSKY, MICHAEL ILYA, SVIRIDOV, DMITRI · 2009 to 2013
$1.6M
Metabolic complications of HIV disease caused by Nef released from HIV-infected cellsR01HL131473 · NHLBI · GEORGE WASHINGTON UNIVERSITY · PI BUKRINSKY, MICHAEL ILYA, SVIRIDOV, DMITRI · 2016 to 2019
$1.6M
Structural characterization of the Nef-calnexin complexR21AI114471 · NIAID · GEORGE WASHINGTON UNIVERSITY · PI BUKRINSKY, MICHAEL ILYA · 2016 to 2017
$436k
HIV-1 Nef regulates activity of the ER chaperone calnexinR21AI108533 · NIAID · GEORGE WASHINGTON UNIVERSITY · PI BUKRINSKY, MICHAEL ILYA · 2014 to 2015
$432k
NCI NIH HHS P30 CA051008NHLBI NIH HHS R01 HL093818NHLBI NIH HHS R01 HL101274NHLBI NIH HHS R01 HL131473NIAID NIH HHS P30 AI117970NIAID NIH HHS R21 AI108533NIAID NIH HHS R21 AI114471
6 · The paper itself

Abstract

objectiveHIV-infected patients are at an increased risk of developing atherosclerosis, in part because of downmodulation and functional impairment of ATP-binding cassette A1 (ABCA1) cholesterol transporter by the HIV-1 protein Nef. The mechanism of this effect involves Nef interacting with an ER chaperone calnexin and disrupting calnexin binding to ABCA1, leading to ABCA1 retention in ER, its degradation and resulting suppression of cholesterol efflux. However, molecular details of Nef-calnexin interaction remained unknown, limiting the translational impact of this finding. APPROACH AND

resultsHere, we used molecular modeling and mutagenesis to characterize Nef-calnexin interaction and to identify small molecule compounds that could block it. We demonstrated that the interaction between Nef and calnexin is direct and can be reconstituted using recombinant proteins in vitro with a binding affinity of 89.1 nmol/L measured by surface plasmon resonance. The cytoplasmic tail of calnexin is essential and sufficient for interaction with Nef, and binds Nef with an affinity of 9.4 nmol/L. Replacing lysine residues in positions 4 and 7 of Nef with alanines abrogates Nef-calnexin interaction, prevents ABCA1 downregulation by Nef, and preserves cholesterol efflux from HIV-infected cells. Through virtual screening of the National Cancer Institute library of compounds, we identified a compound, 1[(7-oxo-7H-benz[de]anthracene-3-yl)amino]anthraquinone, which blocked Nef-calnexin interaction, partially restored ABCA1 activity in HIV-infected cells, and reduced foam cell formation in a culture of HIV-infected macrophages.

conclusionThis study identifies potential targets that can be exploited to block the pathogenic effect of HIV infection on cholesterol metabolism and prevent atherosclerosis in HIV-infected subjects.

Indexed as

Drug DesignMolecular Docking SimulationAnthraquinonesAtherosclerosisATP Binding Cassette Transporter 1Biological TransportCalnexinCholesterolComputer-Aided DesignFoam CellsHEK293 CellsHIV InfectionsHumansHypolipidemic AgentsLysineMutationABCA1 protein, humanAnthraquinonesATP Binding Cassette Transporter 1CalnexinCholesterolHypolipidemic AgentsLysinenef Gene Products, Human Immunodeficiency Virusnef protein, Human immunodeficiency virus 1calnexincholesterol effluxfoam cellHIV-1molecular modelingNefvirtual screening

Identifiers

PMID27470515
PMCPMC5040351
OpenAlexW2485029596

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.