A cell-intrinsic inhibitor of HIV-1 reverse transcription in CD4(+) T cells from elite controllers

Cell Host Microbe. 2014 Jun 11;15(6):717-728. doi: 10.1016/j.chom.2014.05.011.


HIV-1 reverse transcription represents the predominant target for pharmacological inhibition of viral replication, but cell-intrinsic mechanisms that can block HIV-1 reverse transcription in a clinically significant way are poorly defined. We find that effective HIV-1 reverse transcription depends on the phosphorylation of viral reverse transcriptase by host cyclin-dependent kinase (CDK) 2 at a highly conserved Threonine residue. CDK2-dependent phosphorylation increased the efficacy and stability of viral reverse transcriptase and enhanced viral fitness. Interestingly, p21, a cell-intrinsic CDK inhibitor that is upregulated in CD4(+) T cells from "elite controllers," potently inhibited CDK2-dependent phosphorylation of HIV-1 reverse transcriptase and significantly reduced the efficacy of viral reverse transcription. These data suggest that p21 can indirectly block HIV-1 reverse transcription by inhibiting host cofactors supporting HIV-1 replication and identify sites of viral vulnerability that are effectively targeted in persons with natural control of HIV-1 replication.

MeSH terms

  • Amino Acid Sequence
  • CD4-Positive T-Lymphocytes / virology*
  • Case-Control Studies
  • Cyclin-Dependent Kinase 2 / genetics
  • Cyclin-Dependent Kinase 2 / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Enzyme Stability
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism*
  • HIV-1 / physiology
  • Host-Pathogen Interactions
  • Humans
  • Molecular Sequence Data
  • Phosphorylation
  • Reverse Transcription
  • Up-Regulation
  • Virus Replication


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase