دورية أكاديمية
p21 Restricts HIV-1 in Monocyte-Derived Dendritic Cells through the Reduction of Deoxynucleoside Triphosphate Biosynthesis and Regulation of SAMHD1 Antiviral Activity.
| العنوان: | p21 Restricts HIV-1 in Monocyte-Derived Dendritic Cells through the Reduction of Deoxynucleoside Triphosphate Biosynthesis and Regulation of SAMHD1 Antiviral Activity. |
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| المؤلفون: | Valle-Casuso JC; Institut Pasteur, Unité HIV Inflammation et Persistance, Paris, France., Allouch A; Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France., David A; Institut Pasteur, Unité HIV Inflammation et Persistance, Paris, France., Lenzi GM; Center for Drug Discovery, Department of Pediatrics, Emory University School of Medicine, Atlanta, USA., Studdard L; Center for Drug Discovery, Department of Pediatrics, Emory University School of Medicine, Atlanta, USA., Barré-Sinoussi F; Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France., Müller-Trutwin M; Institut Pasteur, Unité HIV Inflammation et Persistance, Paris, France., Kim B; Center for Drug Discovery, Department of Pediatrics, Emory University School of Medicine, Atlanta, USA., Pancino G; Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France., Sáez-Cirión A; Institut Pasteur, Unité HIV Inflammation et Persistance, Paris, France asier.saez-cirion@pasteur.fr. |
| المصدر: | Journal of virology [J Virol] 2017 Nov 14; Vol. 91 (23). Date of Electronic Publication: 2017 Nov 14 (Print Publication: 2017). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Society For Microbiology Original Publication: Baltimore, American Society for Microbiology. |
| مواضيع طبية MeSH: | Cyclin-Dependent Kinase Inhibitor p21/*metabolism , Dendritic Cells/*virology , Deoxyribonucleotides/*biosynthesis , HIV-1/*physiology , Monocytes/*virology , SAM Domain and HD Domain-Containing Protein 1/*metabolism, Antiviral Agents/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; DNA Replication ; Dendritic Cells/physiology ; Deoxyribonucleotides/chemistry ; HIV-1/immunology ; Humans ; Polyphosphates/chemistry ; Polyphosphates/metabolism ; SAM Domain and HD Domain-Containing Protein 1/genetics ; Virus Replication |
| مستخلص: | 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 replication, 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 phosphorylation 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. (Copyright © 2017 American Society for Microbiology.) |
| References: | J Virol. 2005 May;79(9):5386-99. (PMID: 15827153) Breast Cancer Res. 2007;9(3):R33. (PMID: 17535433) Virology. 2013 Feb 20;436(2):247-54. (PMID: 23260109) Nat Rev Cancer. 2015 Sep;15(9):528-39. (PMID: 26299592) Cell Host Microbe. 2013 Apr 17;13(4):441-51. (PMID: 23601106) Br J Haematol. 2002 Jun;117(3):727-34. (PMID: 12028050) J Biol Chem. 1996 Dec 6;271(49):31723-8. (PMID: 8940196) Nat Med. 2012 Nov;18(11):1682-7. (PMID: 22972397) Oncogene. 2006 Aug 28;25(38):5220-7. (PMID: 16936740) J Exp Med. 1986 Jul 1;164(1):280-90. (PMID: 3014036) Curr Top Microbiol Immunol. 2003;276:1-30. (PMID: 12797441) J Virol. 1995 Nov;69(11):6705-11. (PMID: 7474080) J Virol. 2000 Nov;74(21):10074-80. (PMID: 11024136) Nature. 2011 Nov 06;480(7377):379-82. (PMID: 22056990) J Immunol. 2010 Jun 1;184(11):6084-91. (PMID: 20421650) Retrovirology. 2012 Dec 11;9:105. (PMID: 23231760) Nature. 2011 Jun 29;474(7353):658-61. (PMID: 21720370) Retrovirology. 2014 Feb 01;11:12. (PMID: 24485168) J Biol Chem. 2014 Nov 21;289(47):32617-27. (PMID: 25288794) Retrovirology. 2015 Jun 02;12:46. (PMID: 26032178) J Virol. 2009 Dec;83(23):12253-65. (PMID: 19759136) Nat Protoc. 2011 Jun;6(6):806-16. (PMID: 21637200) J Cell Physiol. 2001 Apr;187(1):124-35. (PMID: 11241357) Nat Med. 2016 Oct 6;22(10 ):1074-1075. (PMID: 27711067) PLoS Pathog. 2016 Aug 19;12 (8):e1005829. (PMID: 27541004) Nat Med. 2014 Aug;20(8):936-41. (PMID: 25038827) Cell Host Microbe. 2014 Jun 11;15(6):717-728. (PMID: 24922574) Cell Rep. 2013 Apr 25;3(4):1036-43. (PMID: 23602554) Nucleic Acids Res. 2015 Feb 27;43(4):2466-85. (PMID: 25628363) J Virol. 2006 Mar;80(6):2949-57. (PMID: 16501104) Proc Natl Acad Sci U S A. 2014 May 6;111(18):E1843-51. (PMID: 24753578) J Biol Chem. 2013 Mar 22;288(12):8101-10. (PMID: 23364794) Cell. 2012 May 25;149(5):1023-34. (PMID: 22632967) Mutat Res. 2010 Nov 28;703(1):2-10. (PMID: 20561600) J Virol. 2013 Nov;87(21):11516-24. (PMID: 23966382) Proc Natl Acad Sci U S A. 2004 May 18;101(20):7669-74. (PMID: 15128934) Virology. 2016 Jan 15;488:271-7. (PMID: 26655245) Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):E1322-4. (PMID: 24610778) Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):E1325-6. (PMID: 24834497) Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):E4305-14. (PMID: 25267621) Clin Exp Immunol. 2008 Dec;154(3):365-74. (PMID: 18782327) Curr Cancer Drug Targets. 2006 Aug;6(5):409-31. (PMID: 16918309) Nature. 1993 Dec 16;366(6456):701-4. (PMID: 8259214) Immunity. 1999 Jul;11(1):103-13. (PMID: 10435583) J Immunol. 2006 Nov 1;177(9):6291-300. (PMID: 17056559) EMBO J. 1999 Mar 1;18(5):1223-34. (PMID: 10064589) Virology. 1995 Feb 1;206(2):935-44. (PMID: 7531918) J Clin Invest. 2011 Apr;121(4):1549-60. (PMID: 21403397) Cell. 2014 Jan 16;156(1-2):134-45. (PMID: 24412650) Nat Rev Mol Cell Biol. 2008 Sep;9(9):713-24. (PMID: 18719710) J Biol Chem. 2012 Apr 20;287(17):14280-8. (PMID: 22383524) Nat Immunol. 2012 Feb 12;13(3):223-228. (PMID: 22327569) Nat Immunol. 2011 Apr;12(4):295-303. (PMID: 21358638) Crit Rev Biochem Mol Biol. 2012 Jan-Feb;47(1):50-63. (PMID: 22050358) J Biol Chem. 2004 Dec 3;279(49):51545-53. (PMID: 15452123) Nat Med. 2016 Oct 6;22(10 ):1072-1074. (PMID: 27711056) Retrovirology. 2009 Jun 01;6:51. (PMID: 19486514) Nat Rev Immunol. 2006 Nov;6(11):859-68. (PMID: 17063186) J Immunother. 2009 May;32(4):399-407. (PMID: 19342965) Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):E3997-4006. (PMID: 24082141) Retrovirology. 2006 Nov 08;3:81. (PMID: 17092330) Cancer Immunol Immunother. 2011 Apr;60(4):457-66. (PMID: 21258790) Nature. 2011 May 25;474(7353):654-7. (PMID: 21613998) Viruses. 2010 Aug;2(8):1704-17. (PMID: 21994702) J Biol Chem. 2016 Oct 7;291(41):21407-21413. (PMID: 27566548) Trends Immunol. 2014 Mar;35(3):114-22. (PMID: 24246474) Trends Microbiol. 2015 Nov;23(11):680-92. (PMID: 26439297) Blood. 2011 Jul 28;118(4):955-64. (PMID: 21642597) Retrovirology. 2012 Oct 23;9:87. (PMID: 23092122) PLoS Pathog. 2010 Mar 26;6(3):e1000740. (PMID: 20360840) J Biol Chem. 2012 Jun 22;287(26):21570-4. (PMID: 22589553) J Biol Chem. 2011 Dec 23;286(51):43596-600. (PMID: 22069334) J Exp Med. 1998 Dec 7;188(11):2175-80. (PMID: 9841930) BMC Immunol. 2010 Aug 03;11:41. (PMID: 20682054) |
| معلومات مُعتمدة: | R01 AI049781 United States AI NIAID NIH HHS; R01 GM104198 United States GM NIGMS NIH HHS; R56 AI049781 United States AI NIAID NIH HHS; T32 GM008602 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: HIV replication; HIV-1; SAMHD1; cellular factors; dNTPs; dendritic cells; p21 |
| المشرفين على المادة: | 0 (Antiviral Agents) 0 (Cyclin-Dependent Kinase Inhibitor p21) 0 (Deoxyribonucleotides) 0 (Polyphosphates) EC 3.1.5.- (SAM Domain and HD Domain-Containing Protein 1) EC 3.1.5.- (SAMHD1 protein, human) NU43IAG5BC (triphosphoric acid) |
| تواريخ الأحداث: | Date Created: 20170922 Date Completed: 20171206 Latest Revision: 20220113 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC5686764 |
| DOI: | 10.1128/JVI.01324-17 |
| PMID: | 28931685 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1098-5514 |
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| DOI: | 10.1128/JVI.01324-17 |