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

Awatef Allouch (1) , Annie David (1) , Sarah M. Amie (2) , Hichem Lahouassa (3) , Loic Chartier (4) , Florence Margottin-Goguet (5, 3) , Françoise Barré-Sinoussi (1, 6) , Baek Kim (7, 2) , Asier Saez-Cirion (1) , Gianfranco Pancino (1, 6)

1 Régulation des Infections Rétrovirales
2 Emory University [Atlanta, GA]
3 IC UM3 (UMR 8104 / U1016) - Institut Cochin
4 Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology
5 UPD5 - Université Paris Descartes - Paris 5
6 INSERM - Institut National de la Santé et de la Recherche Médicale
7 Kyung Hee University

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: Cells; Cultured; Cyclin-Dependent Kinase Inhibitor p21; Deoxyribonucleotides; DNA; Complementary; Viral; Down-Regulation; E2F1 Transcription Factor; Gene Expression Regulation; Enzymologic; HIV-1; HIV Infections; Macrophages; Monomeric GTP-Binding Proteins; Ribonucleotide Reductases; Simian Immunodeficiency Virus; Transcription; Genetic; Virus Replication

Domains: Life Sciences [q-bio]; Immunology

Awatef Allouch, Annie David, Sarah M. Amie, Hichem Lahouassa, Loic Chartier, et al.. p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110 (42), pp.E3997--4006. ⟨10.1073/pnas.1306719110⟩. ⟨pasteur-01420537⟩