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Naturally occurring capsid substitutions render HIV-1 cyclophilin A independent in human cells and TRIM-cyclophilin-resistant in Owl monkey cells

Academic Article
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Overview

authors

  • Chatterji, U.
  • Bobardt, M. D.
  • Stanfield, Robyn
  • Ptak, R. G.
  • Pallansch, L. A.
  • Ward, P. A.
  • Jones, M. J.
  • Stoddart, C. A.
  • Scalfaro, P.
  • Dumont, J. M.
  • Besseghir, K.
  • Rosenwirth, B.
  • Gallay, Philippe

publication date

  • 2005

journal

  • Journal of Biological Chemistry  Journal

abstract

  • In this study, we asked if a naturally occurring HIV-1 variant exists that circumvents CypA dependence in human cells. To address this issue, we sought viruses for CypA independence using Debio-025, a cyclosporine A (CsA) analog that disrupts CypA-capsid interaction. Surprisingly, viral variants from the Main group replicate even in the presence of the drug. Sequencing analyses revealed that these viruses encode capsid substitutions within the CypA-binding site (V86P/H87Q/I91V/M96I). When we introduced these substitutions into viruses that normally rely on CypA for replication, these mutants no longer depended on CypA, suggesting that naturally occurring capsid substitutions obviate the need for CypA. This is the first demonstration that isolates from the Main group naturally develop CypA-independent strategies to replicate in human cells. Surprisingly, we found that these capsid substitutions render HIV-1 capable of infecting Owl monkey (OMK) cells that highly restrict HIV-1. OMK cell resistance to HIV-1 is mediated via TRIM-Cyp, which arose from a retrotransposition of CypA into the TRIM5 alpha gene. Interestingly, saturation experiments suggest that the Pro86/Gln87/Val91/Ile96 capsid core is "invisible" to TRIM-Cyp. This study demonstrates that specific capsid substitutions can release HIV-1 from both CypA dependence in human cells and TRIM-Cyp restriction in monkey cells.

subject areas

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Aotidae
  • Binding Sites
  • Blotting, Western
  • Capsid
  • Capsid Proteins
  • Cell Line
  • Cyclophilin A
  • Cyclophilins
  • HIV-1
  • Humans
  • Membrane Proteins
  • Molecular Sequence Data
  • Polymorphism, Genetic
  • Retroelements
  • Time Factors
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M506314200

PubMed ID

  • 16199531
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Additional Document Info

start page

  • 40293

end page

  • 40300

volume

  • 280

issue

  • 48

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