p21 Restricts HIV-1 in Monocyte-Derived Dendritic Cells through the Reduction of Deoxynucleoside Triphosphate Biosynthesis and Regulation of SAMHD1 Antiviral Activity VIRUS-CELL INTERACTIONS crossm
| العنوان: | p21 Restricts HIV-1 in Monocyte-Derived Dendritic Cells through the Reduction of Deoxynucleoside Triphosphate Biosynthesis and Regulation of SAMHD1 Antiviral Activity VIRUS-CELL INTERACTIONS crossm |
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| المؤلفون: | Valle-Casuso, Jose Carlos, Allouch, Awatef, David, Annie, Lenzi, Gina, Studdard, Lydia, Barré-Sinoussi, Françoise, Muller-Trutwin, Michaela, Kim, Baek, Pancino, Gianfranco, Saez-Cirion, Asier |
| المساهمون: | HIV, Inflammation et persistance, Institut Pasteur [Paris], Régulation des Infections Rétrovirales, Emory University [Atlanta, GA], This study was funded by grants from Sidaction (France) to A.S.-C. and the National Institutes of Health (NIH), grants R01 GM104198 and R01 AI049781-01AI049781, to B.K. J.C.V.-C. received postdoctoral financial support from Sidaction and the Roux-Cantarini program at the Institut Pasteur. A.A. received a postdoctoral fellowship from Sidaction, We are grateful to Alexandra Cribier for kindly providing the pSAMHD1 antibody, HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Institut Pasteur [Paris] (IP) |
| المصدر: | Journal of Virology Journal of Virology, American Society for Microbiology, 2017, 91 (23), pp.1324-1341. ⟨10.1128/JVI.01324-17⟩ Journal of Virology, 2017, 91 (23), pp.1324-1341. ⟨10.1128/JVI.01324-17⟩ |
| بيانات النشر: | HAL CCSD, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | MESH: Antiviral Agents, MESH: Humans, p21, MESH: Dendritic Cells, MESH: Deoxyribonucleotides, cellular factors, MESH: Virus Replication, MESH: DNA Replication, MESH: SAM Domain and HD Domain-Containing Protein 1, MESH: Monocytes, SAMHD1, MESH: Cyclin-Dependent Kinase Inhibitor p21, dNTPs, MESH: HIV-1, HIV replication, MESH: Polyphosphates, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV-1, [SDV.IMM]Life Sciences [q-bio]/Immunology, dendritic cells |
| الوصف: | International audience; HIV-1 infection of noncycling cells, such as dendritic cells (DCs), is impaired due to limited availability of deoxynucleoside triphosphates (dNTPs), which are needed for HIV-1 reverse transcription. The levels of dNTPs are tightly regulated during the cell cycle and depend on the balance between dNTP biosynthesis and degradation. SAMHD1 potently blocks HIV-1 replication in DCs, although the underlying mechanism is still unclear. SAMHD1 has been reported to be able to degrade dNTPs and viral nucleic acids, which may both hamper HIV-1 reverse transcription. The relative contribution of these activities may differ in cycling and noncycling cells. Here, we show that inhibition of HIV-1 replication in monocyte-derived DCs (MDDCs) is associated with an increased expression of p21cip1/waf, a cell cycle regulator that is involved in the differentiation and maturation of DCs. Induction of p21 in MDDCs decreases the pool of dNTPs and increases the antiviral active isoform of SAMHD1. Although both processes are complementary in inhibiting HIV-1 replica-tion, the antiviral activity of SAMHD1 in our primary cell model appears to be, at least partially, independent of its dNTPase activity. The reduction in the pool of dNTPs in MDDCs appears rather mostly due to a p21-mediated suppression of several enzymes involved in dNTP synthesis (i.e., RNR2, TYMS, and TK-1). These results are important to better understand the interplay between HIV-1 and DCs and may inform the design of new therapeutic approaches to decrease viral dissemination and improve immune responses against HIV-1. IMPORTANCE DCs play a key role in the induction of immune responses against HIV. However, HIV has evolved ways to exploit these cells, facilitating immune evasion and virus dissemination. We have found that the expression of p21, a cyclin-dependent kinase inhibitor involved in cell cycle regulation and monocyte differentiation and maturation, potentially can contribute to the inhibition of HIV-1 replication in monocyte-derived DCs through multiple mechanisms. p21 decreased the size of the intracellular dNTP pool. In parallel, p21 prevented SAMHD1 phos-phorylation and promoted SAMHD1 dNTPase-independent antiviral activity. Thus, induction of p21 resulted in conditions that allowed the effective inhibition of HIV-1 replication through complementary mechanisms. Overall, p21 appears to be a key regulator of HIV infection in myeloid cells. |
| اللغة: | English |
| تدمد: | 0022-538X 1098-5514 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=dedup_wf_001::c1773310d0076a475afa246ee91eb9cc https://hal-pasteur.archives-ouvertes.fr/pasteur-01959364/file/e01324-17.pdf |
| رقم الأكسشن: | edsair.dedup.wf.001..c1773310d0076a475afa246ee91eb9cc |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 0022538X 10985514 |
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