Cyclin T1 and CDK9 T-loop phosphorylation are downregulated during establishment of HIV-1 latency in primary resting memory CD4+ T cells

J Virol. 2013 Jan;87(2):1211-20. doi: 10.1128/JVI.02413-12. Epub 2012 Nov 14.


P-TEFb, a cellular kinase composed of Cyclin T1 and CDK9, is essential for processive HIV-1 transcription. P-TEFb activity is dependent on phosphorylation of Thr186 in the CDK9 T loop. In resting CD4(+) T cells which are nonpermissive for HIV-1 replication, the levels of Cyclin T1 and T-loop-phosphorylated CDK9 are very low but increase significantly upon cellular activation. Little is known about how P-TEFb activity and expression are regulated in resting central memory CD4(+) T cells, one of the main reservoirs of latent HIV-1. We used an in vitro primary cell model of HIV-1 latency to show that P-TEFb availability in resting memory CD4(+) T cells is governed by the differential expression and phosphorylation of its subunits. This is in contrast to previous observations in dividing cells, where P-TEFb can be regulated by its sequestration in the 7SK RNP complex. We find that resting CD4(+) T cells, whether naïve or memory and independent of their infection status, have low levels of Cyclin T1 and T-loop-phosphorylated CDK9, which increase upon activation. We also show that the decrease in Cyclin T1 protein upon the acquisition of a memory phenotype is in part due to proteasome-mediated proteolysis and likely also to posttranscriptional downregulation by miR-150. We also found that HEXIM1 levels are very low in ex vivo- and in vitro-generated resting memory CD4(+) T cells, thus limiting the sequestration of P-TEFb in the 7SK RNP complex, indicating that this mechanism is unlikely to be a driver of viral latency in this cell type.

Publication types

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

MeSH terms

  • CD4-Positive T-Lymphocytes / virology*
  • Cells, Cultured
  • Cyclin T / metabolism*
  • Cyclin-Dependent Kinase 9 / metabolism*
  • Gene Expression
  • HIV-1 / pathogenicity*
  • HIV-1 / physiology
  • Humans
  • Phosphorylation
  • Virus Latency*


  • Cyclin T
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9