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

Sona Budhiraja1, Marylinda Famiglietti, Alberto Bosque

  • 1Department of Molecular Microbiology and Virology, Baylor College of Medicine, Houston, TX, USA.

Journal of Virology
|November 16, 2012
PubMed

Insights

In resting CD4(+) T cells, low levels of Cyclin T1 and phosphorylated CDK9 limit HIV-1 transcription. Cellular activation increases these factors, impacting viral latency in memory CD4(+) T cells.

Area of Science:

  • Molecular Biology
  • Virology
  • Immunology

Background:

  • P-TEFb (Cyclin T1/CDK9) is crucial for HIV-1 transcription, with activity dependent on CDK9 phosphorylation.
  • Resting CD4(+) T cells harbor latent HIV-1, and P-TEFb regulation in these cells, particularly memory subsets, is poorly understood.

Purpose of the Study:

  • To investigate the regulation of P-TEFb expression and activity in resting memory CD4(+) T cells.
  • To determine the mechanisms controlling P-TEFb availability and its role in HIV-1 latency.

Main Methods:

  • Utilized an in vitro primary cell model of HIV-1 latency.
  • Analyzed P-TEFb subunit expression and phosphorylation in naïve and memory CD4(+) T cells.
  • Investigated the role of proteasomal degradation and microRNA in Cyclin T1 regulation.
  • Assessed HEXIM1 levels and 7SK RNP complex formation.

Main Results:

  • P-TEFb availability in resting memory CD4(+) T cells is governed by differential expression and phosphorylation of its subunits, not 7SK RNP sequestration.
  • Resting CD4(+) T cells (naïve and memory) exhibit low Cyclin T1 and T-loop-phosphorylated CDK9, increasing upon activation.
  • Cyclin T1 downregulation in memory cells involves proteasome-mediated proteolysis and miR-150.
  • Low HEXIM1 levels in memory cells suggest 7SK RNP sequestration is not a primary driver of latency.

Conclusions:

  • P-TEFb regulation in resting memory CD4(+) T cells relies on subunit expression and phosphorylation, distinct from mechanisms in dividing cells.
  • Mechanisms like Cyclin T1 proteolysis and miR-150 contribute to low P-TEFb levels in memory cells, influencing HIV-1 latency.
  • 7SK RNP complex sequestration is unlikely to be the main driver of HIV-1 latency in this cell type.

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