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Journal articles
p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway
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 SAM domain 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.
Keywords :
HIV-1
HIV Infections
Macrophages
Cells
Cultured
Cyclin-Dependent Kinase Inhibitor p21
Deoxyribonucleotides
DNA
Complementary
Viral
Down-Regulation
E2F1 Transcription Factor
Gene Expression Regulation
Enzymologic
Monomeric GTP-Binding Proteins
Ribonucleotide Reductases
Simian Immunodeficiency Virus
Transcription
Genetic
Virus Replication
https://hal-pasteur.archives-ouvertes.fr/pasteur-01420537
Contributor : Marie-Genevieve Guibert <>
Submitted on : Tuesday, December 20, 2016 - 4:59:05 PM
Last modification on : Tuesday, April 21, 2020 - 5:30:10 PM
Contributor : Marie-Genevieve Guibert <>
Submitted on : Tuesday, December 20, 2016 - 4:59:05 PM
Last modification on : Tuesday, April 21, 2020 - 5:30:10 PM
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