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Attenuation of HIV-1 replication in primary human cells with a designed zinc finger transcription factor

Academic Article
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Overview

authors

  • Segal, D. J.
  • Goncalves, J.
  • Eberhardy, S.
  • Swan, C. H.
  • Torbett, Bruce
  • Li, X. L.
  • Barbas III, Carlos

publication date

  • 2004

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Small molecule inhibitors of human immunodeficiency virus, type 1 (HIV-1) have been extremely successful but are associated with a myriad of undesirable effects and require lifelong daily dosing. In this study we explore an alternative approach, that of inducing intracellular immunity using designed, zinc finger-based transcription factors. Three transcriptional repression proteins were engineered to bind sites in the HIV-1 promoter that were expected to be both accessible in chromatin structure and highly conserved in sequence structure among the various HIV-1 subgroups. Transient transfection assays identified one factor, KRAB-HLTR3, as being able to achieve 100-fold repression of an HIV-1 promoter. Specificity of repression was demonstrated by the lack of repression of other promoters. This factor was further shown to repress the replication of several HIV-1 viral strains 10- to 100-fold in T-cell lines and primary human peripheral blood mononuclear cells. Repression was observed for at least 18 days with no significant cytotoxicity. Stable T-cell lines expressing the factor also do not show obvious signs of cytotoxicity. These characteristics present KRAB-HLTR3 as an attractive candidate for development in an intracellular immunization strategy for anti-HIV-1 therapy.

subject areas

  • Base Sequence
  • Binding Sites
  • Blotting, Western
  • Cell Line
  • Cells, Cultured
  • Chromatin
  • DNA
  • DNA-Binding Proteins
  • Electrophoresis, Polyacrylamide Gel
  • Flow Cytometry
  • Genes, Reporter
  • Genetic Vectors
  • HIV Long Terminal Repeat
  • HIV-1
  • HeLa Cells
  • Humans
  • Kinetics
  • Lentivirus
  • Models, Genetic
  • Molecular Sequence Data
  • Plasmids
  • Promoter Regions, Genetic
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • T-Lymphocytes
  • Time Factors
  • Transcription Factors
  • Transcription, Genetic
  • Transfection
  • Virus Replication
  • Zinc Fingers
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M400349200

PubMed ID

  • 14734553
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Additional Document Info

start page

  • 14509

end page

  • 14519

volume

  • 279

issue

  • 15

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