title: The miRNA miR-34a enhances HIV-1 replication by targeting PNUTS/PPP1R10, which negatively regulates HIV-1 transcriptional complex formation.
abstract: 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.
authors.affiliation: Laboratory of Virology, National Institute of Immunology (NII), New Delhi, India.
authors.forename: Richa
authors.initials: R
authors.lastname: Kapoor
authors.affiliation: Laboratory of Virology, National Institute of Immunology (NII), New Delhi, India.
authors.forename: Sakshi
authors.initials: S
authors.lastname: Arora
authors.affiliation: Laboratory of Virology, National Institute of Immunology (NII), New Delhi, India.
authors.forename: Sanket S
authors.initials: SS
authors.lastname: Ponia
authors.affiliation: Laboratory of Virology, National Institute of Immunology (NII), New Delhi, India.
authors.forename: Binod
authors.initials: B
authors.lastname: Kumar
authors.affiliation: Laboratory of Cell Death & Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad, India.
authors.forename: Subbareddy
authors.initials: S
authors.lastname: Maddika
authors.affiliation: Laboratory of Virology, National Institute of Immunology (NII), New Delhi, India akhil@nii.res.in akhil_banerjea@yahoo.com.
authors.forename: Akhil C
authors.initials: AC
authors.lastname: Banerjea
mesh_terms: D056906:Cyclin T / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology*; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000502:physiology; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D014158:Transcription, Genetic; D015854:Up-Regulation; D014779:Virus Replication / Q000235:genetics* / Q000502:physiology*
chemical_list: C503684:CCNT1 protein, human; D056906:Cyclin T; D004268:DNA-Binding Proteins; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; C110225:PPP1R10 protein, human; D016601:RNA-Binding Proteins; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9
keywords: CDK9; HIV; PNUTS; cyclin T1; miR-34a; p24