Mobilization-competent Lentiviral Vector-mediated Sustained Transcriptional Modulation of HIV-1 Expression.
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.
Turner
Anne-Marie W
AM
Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
De La Cruz
Justin
J
Morris
Kevin V
KV
D060565:Argonaute Proteins; D047369:Chromatin Immunoprecipitation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics*; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D014158:Transcription, Genetic / Q000235:genetics*
C115848:AGO1 protein, human; D060565:Argonaute Proteins; C000717967:DNMT3A protein, human; D039642:Eukaryotic Initiation Factors; D006657:Histones; D016328:NF-kappa B; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A