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

Awatef Allouch1, Annie David, Sarah M Amie

  • 1Unité de Régulation des Infections Rétrovirales, Institut Pasteur, 75015 Paris, France.

Proceedings of the National Academy of Sciences of the United States of America
|October 2, 2013
PubMed

Insights

The cyclin-dependent kinase inhibitor p21 restricts HIV-1 replication in macrophages by depleting deoxyribonucleotides (dNTPs) through a novel pathway. This impacts viral cDNA synthesis and offers new therapeutic targets for HIV.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Macrophages are key targets for HIV-1, contributing to disease progression.
  • Previous work showed p21 inhibits HIV-1 and primate lentivirus replication in macrophages by impairing reverse transcription.

Purpose of the Study:

  • To elucidate the p21-mediated restriction mechanisms against HIV-1 and SIVmac in macrophages.
  • To identify the specific cellular pathways involved in p21's antiviral activity.

Main Methods:

  • Investigated the effect of p21 on intracellular deoxyribonucleotide (dNTP) pools during lentiviral infection.
  • Analyzed the expression of ribonucleotide reductase (RNR) subunits and transcription factors like E2F1.
  • Utilized human monocyte-derived macrophages and HIV-1/SIVmac infection models.

Main Results:

  • p21 reduces intracellular dNTP levels in macrophages, impairing HIV-1 and SIVmac reverse transcription via a SAMHD1-independent pathway.
  • p21 down-regulates RNR2 expression, a key enzyme in dNTP biosynthesis.
  • p21 inhibits RNR2 transcription by repressing the E2F1 transcription factor.

Conclusions:

  • p21 restricts primate lentivirus replication by inhibiting dNTP synthesis through the RNR2/E2F1 pathway.
  • This cellular mechanism presents a novel target for developing anti-HIV therapies.

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