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Functional mechanisms of the cellular prion protein (PrPC) associated anti-HIV-1 properties

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Abstract

The cellular prion protein PrPC/CD230 is a GPI-anchor protein highly expressed in cells from the nervous and immune systems and well conserved among vertebrates. In the last decade, several studies suggested that PrPC displays antiviral properties by restricting the replication of different viruses, and in particular retroviruses such as murine leukemia virus (MuLV) and the human immunodeficiency virus type 1 (HIV-1). In this context, we previously showed that PrPC displays important similarities with the HIV-1 nucleocapsid protein and found that PrPC expression in a human cell line strongly reduced HIV-1 expression and virus production. Using different PrPC mutants, we report here that the anti-HIV-1 properties are mostly associated with the amino-terminal 24-KRPKP-28 basic domain. In agreement with its reported RNA chaperone activity, we found that PrPC binds to the viral genomic RNA of HIV-1 and negatively affects its translation. Using a combination of biochemical and cell imaging strategies, we found that PrPC colocalizes with the virus assembly machinery at the plasma membrane and at the virological synapse in infected T cells. Depletion of PrPC in infected T cells and microglial cells favors HIV-1 replication, confirming its negative impact on the HIV-1 life cycle.

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Abbreviations

HIV:

Human immunodeficiency virus

GPI:

Glycosyl phosphatidyl inositol

DRMs:

Detergent-resistant microdomains

TEMs:

Tetraspanin-enriched microdomains

TNTs:

Tuneling nanotubes

UTR:

Untranslated region

GFP:

Green fluorescent protein

OR:

Octa repeat

HC:

Hydrophobic core

TM:

Transmembrane

PLAP:

Placental alkaline phosphatase

VSVg:

Vesicular stomatitis virus glycoprotein

LVs:

Lentivectors

ELISA:

Enzyme-linked immunosorbent assay

KD:

Knock down

FACS:

Fluorescent activated cell sorter

WT:

Wild type

RT:

Reverse transcriptase

FL:

Full length

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Acknowledgments

We thank Ramanujan Hegde, David Harris, Paul Bieniasz, David Westaway, Jeremy Luban, Serge Bénichou, Didier Trono and Hybridolab for kindly providing biological materials. We thank Olivier Schwartz, Clarisse Berlioz-Torrent and Renaud Mahieux for materials, discussions and help. We thank Robin Buckland and Jenny T. Miller for carefully reading the manuscript. We acknowledge the PLATIM microscope platform at ENS Lyon (SFR Biosciences Gerland–Lyon Sud UMS34444/US8, France). This work was supported by the CNRS, INSERM and GIS-Prion. RSR and TO received grant support from ANRS and Conycit. We thank the ANR program EXOPRION (to PL and GR) for its essential contribution to the definitive version of this work.

Author information

Authors and Affiliations

  1. Université de Lyon, 69000, Lyon, France

    Sandrine Alais, Ricardo Soto-Rifo, Vincent Balter, Henri Gruffat, Evelyne Manet, Laurent Schaeffer, Jean Luc Darlix, Andrea Cimarelli, Théophile Ohlmann & Pascal Leblanc

  2. Human virology department, INSERM U758, 69007, Lyon, France

    Sandrine Alais, Ricardo Soto-Rifo, Henri Gruffat, Evelyne Manet, Jean Luc Darlix, Andrea Cimarelli, Théophile Ohlmann & Pascal Leblanc

  3. Ecole Normale Supérieure de Lyon, 69007, Lyon, France

    Sandrine Alais, Ricardo Soto-Rifo, Vincent Balter, Henri Gruffat, Evelyne Manet, Laurent Schaeffer, Jean Luc Darlix, Andrea Cimarelli, Théophile Ohlmann & Pascal Leblanc

  4. CNRS UMR 5276 “Laboratoire de Géologie de Lyon”, Lyon, France

    Vincent Balter

  5. Laboratoire de Biologie Moléculaire de la Cellule (LBMC) UMR5239 CNRS/ENS/Université de Lyon/HCL, Ecole Normale Supérieure de Lyon, 69007, Lyon, France

    Laurent Schaeffer & Pascal Leblanc

  6. Structure and Membrane Compartments and PICT-IBiSA, Institut Curie, CNRS-UMR144, 12 Rue Lhomond, 75005, Paris, France

    Graça Raposo

Authors
  1. Sandrine Alais
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  2. Ricardo Soto-Rifo
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  3. Vincent Balter
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  4. Henri Gruffat
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  5. Evelyne Manet
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  6. Laurent Schaeffer
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  7. Jean Luc Darlix
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  8. Andrea Cimarelli
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  9. Graça Raposo
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  10. Théophile Ohlmann
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  11. Pascal Leblanc
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Corresponding author

Correspondence to Pascal Leblanc.

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Alais, S., Soto-Rifo, R., Balter, V. et al. Functional mechanisms of the cellular prion protein (PrPC) associated anti-HIV-1 properties. Cell. Mol. Life Sci. 69, 1331–1352 (2012). https://doi.org/10.1007/s00018-011-0879-z

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  • DOI: https://doi.org/10.1007/s00018-011-0879-z

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