About this item:

134 Views | 112 Downloads

Author Notes:

To whom correspondence may be addressed. E-mail: a.allouch@sns.it or gianfranco.pancino@pasteur.fr

A.A. and G.P. designed research; A.A., A.D., S.M.A., B.K., and A.S.-C. performed research; H.L. and F.M.-G. contributed new reagents/analytic tools; A.A., A.D., S.M.A., H.L., L.C., F.M.-G., F.B.-S., B.K., A.S.-C., and G.P. analyzed data; and A.A. and G.P. wrote the paper.

The authors declare no conflict of interest.

Subjects:

Research Funding:

We thank Beatrice Jacquelin (Institut Pasteur) for providing the SIVmac251 viral stock. This study was funded by Sidaction, France, and National Institutes of Health (NIH) Grant AI049781 (to B.K.).

A.A. received a postdoctoral fellowship from Sidaction, and S.M.A. was supported by NIH Training Grant GM068411.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • HUMAN-IMMUNODEFICIENCY-VIRUS
  • CYCLIN-DEPENDENT KINASES
  • CD4(+) T-CELLS
  • REVERSE TRANSCRIPTION
  • DEOXYNUCLEOSIDE TRIPHOSPHATES
  • SAMHD1 RESTRICTS
  • DNA-REPLICATION
  • GENE-EXPRESSION
  • E2F ACTIVITY
  • TYPE-1 INFECTION

p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway

Tools:

Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 110, Number 42

Publisher:

, Pages E3997-E4006

Type of Work:

Article | Final Publisher PDF

Abstract:

Macrophages are a major target cell for HIV-1, and their infection contributes to HIV pathogenesis. We have previously shown that the cyclin-dependent kinase inhibitor p21 inhibits the replication of HIV-1 and other primate lentiviruses in human monocyte-derived macrophages by impairing reverse transcription of the viral genome. In the attempt to understand the p21-mediated restriction mechanisms, we found that p21 impairs HIV-1 and simian immunodeficiency virus (SIV)mac reverse transcription in macrophages by reducing the intracellular deoxyribonucleotide (dNTP) pool to levels below those required for viral cDNA synthesis by a SAMdomain and HD domain-containing protein 1 (SAMHD1)-independent pathway. We found that p21 blocks dNTP biosynthesis by down-regulating the expression of the RNR2 subunit of ribonucleotide reductase, an enzyme essential for the reduction of ribonucleotides to dNTP. p21 inhibits RNR2 transcription by repressing E2F1 transcription factor, its transcriptional activator. Our findings unravel a cellular pathway that restricts HIV-1 and other primate lentiviruses by affecting dNTP synthesis, thereby pointing to new potential cellular targets for anti-HIV therapeutic strategies.
Export to EndNote