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PMID: 19066594 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Mobilization-competent Lentiviral Vector-mediated Sustained Transcriptional Modulation of HIV-1 Expression.

Molecular therapy : the journal of the American Society of Gene Therapy ·Vol. 17 ·No. 2 ·2009-02-00 ·Pages 360-8

Turner AM, De La Cruz J, Morris KV

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.

MeSH Terms
Argonaute Proteins Chromatin Immunoprecipitation DNA (Cytosine-5-)-Methyltransferases/metabolism DNA Methylation DNA Methyltransferase 3A Eukaryotic Initiation Factors/metabolism Gene Expression Regulation, Viral/genetics Genetic Vectors/genetics HIV Long Terminal Repeat/genetics HIV-1/genetics Histones/metabolism Lentivirus/genetics NF-kappa B/metabolism RNA Interference Transcription, Genetic/genetics
Chemicals
AGO1 protein, human Argonaute Proteins DNMT3A protein, human Eukaryotic Initiation Factors Histones NF-kappa B DNA (Cytosine-5-)-Methyltransferases DNA Methyltransferase 3A
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Turner Anne-Marie W
Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
De La Cruz Justin
Morris Kevin V
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Article Info
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
Abbr.
Mol Ther
ISSN
1525-0024
DOI
10.1038/mt.2008.268
Published
2009-02-00
Epub
2008-00-09
Pages
360-8
Language
English
Region
United States
NLM ID
100890581
PMCID
PMC2835059
Subset
IM
Grants
NIAID NIH HHS · P30 AI036214 · United States
NHLBI NIH HHS · R01 HL083473 · United States
NIAID NIH HHS · 5 P30 AI36214 · United States
NHLBI NIH HHS · R01 HL083473-02 · United States
External Links
PubMed source DOI: 10.1038/mt.2008.268 PMC Full Text View journal details
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