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.
Publication types
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Clinical Trial
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
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DNA, Complementary / biosynthesis
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DNA, Complementary / genetics
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DNA, Viral / biosynthesis
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DNA, Viral / genetics
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Deoxyribonucleotides / biosynthesis*
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Deoxyribonucleotides / genetics
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Down-Regulation / genetics
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E2F1 Transcription Factor / genetics
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E2F1 Transcription Factor / metabolism
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Gene Expression Regulation, Enzymologic*
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HIV Infections / metabolism*
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HIV Infections / therapy
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HIV Infections / virology
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HIV-1 / physiology*
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Macrophages / metabolism*
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Macrophages / virology
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Monomeric GTP-Binding Proteins / genetics
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Monomeric GTP-Binding Proteins / metabolism
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Ribonucleotide Reductases / biosynthesis*
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Ribonucleotide Reductases / genetics
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SAM Domain and HD Domain-Containing Protein 1
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Simian Immunodeficiency Virus / physiology
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Transcription, Genetic / genetics
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Virus Replication / physiology*
Substances
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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DNA, Complementary
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DNA, Viral
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Deoxyribonucleotides
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E2F1 Transcription Factor
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E2F1 protein, human
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Ribonucleotide Reductases
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ribonucleotide reductase R2 subunit
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SAM Domain and HD Domain-Containing Protein 1
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SAMHD1 protein, human
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Monomeric GTP-Binding Proteins