HIV TAR miRNA, Latency and Cell Survival Open Access
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The integrated proviral HIV-1 DNA, along with the specific chromatinized environment in which integration takes place allows for the coordinated regulation of viral transcription and replication. This work demonstrates that HIV-1 produces a microRNA from the TAR element found at the 5' end of all viral transcripts. This microRNA is capable of regulating viral transcription through chromatin remodeling. These findings suggest a role for the HIV-1 TAR miRNA in regulating viral latency. HIV-1 TAR derived miRNA was detected in infected cell lines and primary cells via RNase protection. Reporter analysis indicates that TAR miRNA can downregulate LTR driven transcription and recruits chromatin remodeling factors to the viral promoter. I have further analyzed what specific factors are recruited by the HIV-1 miRNA. Additionally, changes in cellular gene expression due to TAR miRNA were measured by microarray and western blot. I have also determined that the TAR miRNA protects infected cells from apoptosis by down-regulating cellular genes involved in apoptosis. This suggests a model wherein basal expression of viral RNA leads to the accumulation of short TAR-containing transcripts that are acted upon by Dicer to generate a viral miRNA. This miRNA feeds back on the LTR and helps to maintain the latent state. Additionally, the miRNA alters cellular gene expression to prevent apoptosis and thereby maintain the latent pool. This model is in keeping with the alteration of chromatin structure during activation of viral transcription by Tat.