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Mobilization-competent lentiviral vector-mediated sustained transcriptional modulation of HIV-1 expression

Academic Article
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Overview

related to degree

  • Turner, Anne Marie, Ph.D. in Biology, Scripps Research 2006 - 2011

authors

  • Turner, Anne Marie
  • De La Cruz, J.
  • Morris, Kevin

publication date

  • February 2009

journal

  • Molecular Therapy  Journal

abstract

  • Current anti-HIV-1 strategies reduce replication through targeting of viral proteins and RNA; meanwhile, targeting at the level of the integrated provirus has been less explored. We show here that mobilization-competent vectors containing small noncoding RNAs targeted to transcriptionally active regions of the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) can take advantage of integrated virus and modulate HIV-1 replication. Transcriptional silencing of HIV-1 correlates with an increase in silent-state epigenetic marks including histone and DNA methylation, a loss of nuclear factor-kappaB (NF-kappaB) recruitment, and requires Argonaute 1 (Ago-1), histone deacetylase 1 (HDAC-1), and DNA methyltransferase 3a (DNMT3a) localization to the LTR. Long-term suppression of the virus was observed for 1 month with no evidence of viral resistance. These data show that RNA-directed transcriptional silencing of HIV-1 can be delivered by a mobilization-competent vector, suggesting that this system could be used to target long-term selective pressures on conserved promoter elements to evolve less pathogenic variants of HIV-1.

subject areas

  • Argonaute Proteins
  • Chromatin Immunoprecipitation
  • DNA (Cytosine-5-)-Methyltransferase
  • DNA Methylation
  • Eukaryotic Initiation Factors
  • Gene Expression Regulation, Viral
  • Genetic Vectors
  • HIV Long Terminal Repeat
  • HIV-1
  • Histones
  • Lentivirus
  • NF-kappa B
  • RNA Interference
  • Transcription, Genetic
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Identity

PubMed Central ID

  • PMC2835059

International Standard Serial Number (ISSN)

  • 1525-0016

Digital Object Identifier (DOI)

  • 10.1038/mt.2008.268

PubMed ID

  • 19066594
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Additional Document Info

start page

  • 360

end page

  • 368

volume

  • 17

issue

  • 2

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