miR-198 Inhibits HIV-1 Gene Expression and Replication in Monocytes and Its Mechanism of Action Appears to Involve Repression of Cyclin T1

PLoS Pathog. 2009 Jan;5(1):e1000263. doi: 10.1371/journal.ppat.1000263. Epub 2009 Jan 16.

Abstract

Cyclin T1 is a regulatory subunit of a general RNA polymerase II elongation factor known as P-TEFb. Cyclin T1 is also required for Tat transactivation of HIV-1 LTR-directed gene expression. Translation of Cyclin T1 mRNA has been shown to be repressed in human monocytes, and this repression is relieved when cells differentiate to macrophages. We identified miR-198 as a microRNA (miRNA) that is strongly down-regulated when monocytes are induced to differentiate. Ectopic expression of miR-198 in tissue culture cells reduced Cyclin T1 protein expression, and plasmid reporter assays verified miR-198 target sequences in the 3' untranslated region (3'UTR) of Cyclin T1 mRNA. Cyclin T1 protein levels increased when an inhibitor of miR-198 was transfected into primary monocytes, and overexpression of miR-198 in primary monocytes repressed the normal up-regulation of Cyclin T1 during differentiation. Expression of an HIV-1 proviral plasmid and HIV-1 replication were repressed in a monocytic cell line upon overexpression of miR-198. Our data indicate that miR-198 functions to restrict HIV-1 replication in monocytes, and its mechanism of action appears to involve repression of Cyclin T1 expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions / drug effects
  • Cell Differentiation
  • Cell Line
  • Cyclin T
  • Cyclins / drug effects*
  • Down-Regulation
  • HIV Infections / genetics
  • HIV Long Terminal Repeat
  • HIV-1 / genetics*
  • Humans
  • Macrophages / virology
  • MicroRNAs / physiology*
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Monocytes / virology*
  • RNA, Messenger / metabolism
  • Virus Replication / genetics

Substances

  • 3' Untranslated Regions
  • CCNT1 protein, human
  • Cyclin T
  • Cyclins
  • MIRN198 microRNA, human
  • MicroRNAs
  • RNA, Messenger