HIV-1 relies heavily on the host cellular machinery for its replication. During infection, HIV-1 is known to modulate the host-cell miRNA profile. One of the miRNAs, miR-34a, is up-regulated by HIV-1 in T-cells as suggested by miRNA microarray studies. However, the functional consequences and the mechanism behind this phenomenon were not explored. The present study shows that HIV-1 enhances miR-34a in a time-dependent manner in T-cells. Our overexpression and knockdown-based experimental results suggest that miR-34a promotes HIV-1 replication in T-cells. Hence, there is a positive feedback loop between miR-34a and HIV-1 replication. We show that the mechanism of action of miR-34a in HIV-1 replication involves a cellular protein, the phosphatase 1 nuclear-targeting subunit (PNUTS). PNUTS expression levels decrease with the progression of HIV-1 infection in T-cells. Also, the overexpression of PNUTS potently inhibits HIV-1 replication in a dose-dependent manner. We report for the first time that PNUTS negatively regulates HIV-1 transcription by inhibiting the assembly of core components of the transcription elongation factor P-TEFb, i.e. cyclin T1 and CDK9. Thus, HIV-1 increases miR-34a expression in cells to overcome the inhibitory effect of PNUTS on HIV-1 transcription. So, the present study provides new mechanistic details with regard to our understanding of a complex interplay between miR-34a and the HIV-1 transcription machinery involving PNUTS.
The miRNA miR-34a enhances HIV-1 replication by targeting PNUTS/PPP1R10, which negatively regulates HIV-1 transcriptional complex formation
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Richa Kapoor, Sakshi Arora, Sanket S. Ponia, Binod Kumar, Subbareddy Maddika, Akhil C. Banerjea; The miRNA miR-34a enhances HIV-1 replication by targeting PNUTS/PPP1R10, which negatively regulates HIV-1 transcriptional complex formation. Biochem J 15 September 2015; 470 (3): 293–302. doi: https://doi.org/10.1042/BJ20150700
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