1887

Abstract

The connection between the repression of human immunodeficiency virus type 1(HIV-1) transcription and the resting CD4+ T cell state suggests that the host transcription factors involved in the active maintenance of lymphocyte quiescence are likely to repress the viral transactivator, Tat, thereby restricting HIV-1 transcription. In this study, we analysed the interplay between Tat and the forkhead box transcription factors, FoxO1 and FoxO4. We show that FoxO1 and FoxO4 antagonize Tat-mediated transactivation of HIV-1 promoter through the repression of Tat protein expression. No effect was observed on the expression of two HIV-1 accessory proteins, Vif and Vpr. Unexpectedly, we found that FoxO1 and FoxO4 expression causes a strong dose-dependent post-transcriptional suppression of Tat mRNA, indicating that FoxO should effectively inhibit HIV-1 replication by destabilizing Tat mRNA and suppressing Tat-mediated HIV-1 transcription. In accordance with this, we observed that the Tat mRNA half-life is reduced by FoxO4 expression. The physiological relevance of our findings was validated using the J-Lat 10.6 model of latently infected cells. We demonstrated that the overexpression of a constitutively active FoxO4-TM mutant antagonized HIV-1 transcription reactivation in response to T cell activators, such as TNF- or PMA. Altogether, our findings demonstrate that FoxO factors can control HIV-1 transcription and provide new insights into their potential role during the establishment of HIV-1 latency.

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2017-07-01
2024-10-03
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References

  1. Alexaki A, Wigdahl B. HIV-1 infection of bone marrow hematopoietic progenitor cells and their role in trafficking and viral dissemination. PLoS Pathog 2008; 4:e1000215 [View Article][PubMed]
    [Google Scholar]
  2. Williams SA, Greene WC. Regulation of HIV-1 latency by T-cell activation. Cytokine 2007; 39:63–74 [View Article][PubMed]
    [Google Scholar]
  3. Schiralli Lester GM, Henderson AJ. Mechanisms of HIV transcriptional regulation and their contribution to Latency. Mol Biol Int 2012; 2012:1–11 [View Article]
    [Google Scholar]
  4. Siliciano RF, Greene WC, HIV latency, Latency HIV. Cold Spring Harb Perspect Med 2011; 1:a007096 [CrossRef]
    [Google Scholar]
  5. Eisele E, Siliciano RF. Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity 2012; 37:377–388 [View Article][PubMed]
    [Google Scholar]
  6. Nabel G, Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 1987; 326:711–713 [View Article][PubMed]
    [Google Scholar]
  7. Lassen KG, Bailey JR, Siliciano RF. Analysis of human immunodeficiency virus type 1 transcriptional elongation in resting CD4+ T cells in vivo. J Virol 2004; 78:9105–9114 [View Article][PubMed]
    [Google Scholar]
  8. Winslow BJ, Pomerantz RJ, Bagasra O, Trono D. HIV-1 latency due to the site of proviral integration. Virology 1993; 196:849–854 [View Article][PubMed]
    [Google Scholar]
  9. Jordan A, Defechereux P, Verdin E. The site of HIV-1 integration in the human genome determines basal transcriptional activity and response to Tat transactivation. Embo J 2001; 20:1726–1738 [View Article][PubMed]
    [Google Scholar]
  10. Jordan A, Bisgrove D, Verdin E. HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. Embo J 2003; 22:1868–1877 [View Article][PubMed]
    [Google Scholar]
  11. Lewinski MK, Bisgrove D, Shinn P, Chen H, Hoffmann C et al. Genome-wide analysis of chromosomal features repressing human immunodeficiency virus transcription. J Virol 2005; 79:6610–6619 [View Article][PubMed]
    [Google Scholar]
  12. Kao SY, Calman AF, Luciw PA, Peterlin BM. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature 1987; 330:489–493 [View Article][PubMed]
    [Google Scholar]
  13. Tripathy MK, Abbas W, Herbein G. Epigenetic regulation of HIV-1 transcription. Epigenomics 2011; 3:487–502 [View Article][PubMed]
    [Google Scholar]
  14. Wightman F, Ellenberg P, Churchill M, Lewin SR. HDAC inhibitors in HIV. Immunol Cell Biol 2012; 90:47–54 [View Article][PubMed]
    [Google Scholar]
  15. Katoh M, Katoh M. Human FOX gene family (Review). Int J Oncol 2004; 25:1495–1500 [View Article][PubMed]
    [Google Scholar]
  16. Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 2005; 24:7410–7425 [View Article][PubMed]
    [Google Scholar]
  17. Burgering BM. A brief introduction to FOXOlogy. Oncogene 2008; 27:2258–2262 [View Article][PubMed]
    [Google Scholar]
  18. Tothova Z, Gilliland DG. FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell 2007; 1:140–152 [View Article][PubMed]
    [Google Scholar]
  19. Ouyang W, Beckett O, Flavell RA, Li MO, Mo L. An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. Immunity 2009; 30:358–371 [View Article][PubMed]
    [Google Scholar]
  20. Becker T, Loch G, Beyer M, Zinke I, Aschenbrenner AC et al. FOXO-dependent regulation of innate immune homeostasis. Nature 2010; 463:369–373 [View Article][PubMed]
    [Google Scholar]
  21. Fabre S, Lang V, Bismuth G. [PI3-kinase: linking immunological synapse to T-cell proliferation]. Med Sci 2006; 22:872–877 [View Article][PubMed]
    [Google Scholar]
  22. Freitas AA, Rocha B. Homeostasis of naive T cells: the Foxo that fixes. Nat Immunol 2009; 10:133–134 [View Article][PubMed]
    [Google Scholar]
  23. Su D, Coudriet GM, Hyun Kim D, Lu Y, Perdomo G et al. FoxO1 links insulin resistance to proinflammatory cytokine IL-1β production in macrophages. Diabetes 2009; 58:2624–2633 [View Article][PubMed]
    [Google Scholar]
  24. Seiler F, Hellberg J, Lepper PM, Kamyschnikow A, Herr C et al. FOXO transcription factors regulate innate immune mechanisms in respiratory epithelial cells. J Immunol 2013; 190:1603–1613 [View Article][PubMed]
    [Google Scholar]
  25. Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007; 128:325–339 [View Article][PubMed]
    [Google Scholar]
  26. Kerdiles YM, Beisner DR, Tinoco R, Dejean AS, Castrillon DH et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat Immunol 2009; 10:176–184 [View Article][PubMed]
    [Google Scholar]
  27. Kerdiles YM, Stone EL, Beisner DR, Beisner DL, Mcgargill MA, Ch'en IL et al. Foxo transcription factors control regulatory T cell development and function. Immunity 2010; 33:890–904 [View Article][PubMed]
    [Google Scholar]
  28. Hedrick SM. The cunning little vixen: foxo and the cycle of life and death. Nat Immunol 2009; 10:1057–1063 [View Article][PubMed]
    [Google Scholar]
  29. Dejean AS, Beisner DR, Ch'en IL, Kerdiles YM, Babour A et al. Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells. Nat Immunol 2009; 10:504–513 [View Article][PubMed]
    [Google Scholar]
  30. Lei CQ, Zhang Y, Xia T, Jiang LQ, Zhong B et al. FoxO1 negatively regulates cellular antiviral response by promoting degradation of IRF3. J Biol Chem 2013; 288:12596–12604 [View Article][PubMed]
    [Google Scholar]
  31. Litvak V, Ratushny AV, Lampano AE, Schmitz F, Huang AC et al. A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses. Nature 2012; 490:421–425 [View Article][PubMed]
    [Google Scholar]
  32. Oteiza A, Mechti N. Control of FoxO4 activity and cell survival by TRIM22 directs TLR3-Stimulated cells toward IFN type I Gene Induction or apoptosis. J Interferon Cytokine Res 2015; 35:859–874 [View Article][PubMed]
    [Google Scholar]
  33. Fan W, Morinaga H, Kim JJ, Bae E, Spann NJ et al. FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. Embo J 2010; 29:4223–4236 [View Article][PubMed]
    [Google Scholar]
  34. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P et al. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 1999; 96:857–868 [View Article][PubMed]
    [Google Scholar]
  35. Kops GJ, de Ruiter ND, de Vries-Smits AM, Powell DR, Bos JL et al. Direct control of the forkhead transcription factor AFX by protein kinase B. Nature 1999; 398:630–634 [View Article][PubMed]
    [Google Scholar]
  36. Matsuzaki H, Ichino A, Hayashi T, Yamamoto T, Kikkawa U. Regulation of intracellular localization and transcriptional activity of FOXO4 by protein kinase B through phosphorylation at the motif sites conserved among the FOXO family. J Biochem 2005; 138:485–491 [View Article][PubMed]
    [Google Scholar]
  37. Oteiza A, Mechti N. The human T-cell leukemia virus type 1 oncoprotein tax controls forkhead box O4 activity through degradation by the proteasome. J Virol 2011; 85:6480–6491 [View Article][PubMed]
    [Google Scholar]
  38. Dejean AS, Hedrick SM, Kerdiles YM. Highly specialized role of forkhead box O transcription factors in the immune system. Antioxid Redox Signal 2011; 14:663–674 [View Article][PubMed]
    [Google Scholar]
  39. Litvak V, Ratushny AV, Lampano AE, Schmitz F, Huang AC et al. A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses. Nature 2012; 490:421–425 [View Article][PubMed]
    [Google Scholar]
  40. Furukawa-Hibi Y, Yoshida-Araki K, Ohta T, Ikeda K, Motoyama N. FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress. J Biol Chem 2002; 277:26729–26732 [View Article][PubMed]
    [Google Scholar]
  41. Tang TT, Lasky LA. The forkhead transcription factor FOXO4 induces the down-regulation of hypoxia-inducible factor 1 α by a von Hippel-Lindau protein-independent mechanism. J Biol Chem 2003; 278:30125–30135 [View Article][PubMed]
    [Google Scholar]
  42. Hatta M, Cirillo LA. Chromatin opening and stable perturbation of core histone: DNA contacts by FoxO1. J Biol Chem 2007; 282:35583–35593 [View Article][PubMed]
    [Google Scholar]
  43. Emerling BM, Weinberg F, Liu JL, Mak TW, Chandel NS. PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through forkhead transcription factor 3a (FOXO3a). Proc Natl Acad Sci USA 2008; 105:2622–2627 [View Article][PubMed]
    [Google Scholar]
  44. Sivakumaran H, van der Horst A, Fulcher AJ, Apolloni A, Lin MH et al. Arginine methylation increases the stability of human immunodeficiency virus type 1 Tat. J Virol 2009; 83:11694–11703 [View Article][PubMed]
    [Google Scholar]
  45. Zhang L, Qin J, Li Y, Wang J, He Q et al. Modulation of the stability and activities of HIV-1 Tat by its ubiquitination and carboxyl-terminal region. Cell Biosci 2014; 4:61 [View Article][PubMed]
    [Google Scholar]
  46. Wan Z, Chen X. Triptolide inhibits human immunodeficiency virus type 1 replication by promoting proteasomal degradation of tat protein. Retrovirology 2014; 11:88 [View Article][PubMed]
    [Google Scholar]
  47. Hong HW, Lee SW, Myung H. Induced degradation of Tat by nucleocapsid (NC) via the proteasome pathway and its effect on HIV transcription. Viruses 2013; 5:1143–1152 [View Article][PubMed]
    [Google Scholar]
  48. Gargano B, Fiorillo M, Amente S, Majello B, Lania L. p14ARF is capable of promoting HIV-1 tat degradation. Cell Cycle 2008; 7:1433–1439 [View Article][PubMed]
    [Google Scholar]
  49. de Keizer PL, Packer LM, Szypowska AA, Riedl-Polderman PE, van den Broek NJ et al. Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence. Cancer Res 2010; 70:8526–8536 [View Article][PubMed]
    [Google Scholar]
  50. Chun TW, Justement JS, Lempicki RA, Yang J, Dennis G et al. Gene expression and viral prodution in latently infected, resting CD4+ T cells in viremic versus aviremic HIV-infected individuals. Proc Natl Acad Sci USA 2003; 100:1908–1913 [View Article][PubMed]
    [Google Scholar]
  51. Lassen K, Han Y, Zhou Y, Siliciano J, Siliciano RF. The multifactorial nature of HIV-1 latency. Trends Mol Med 2004; 10:525–531 [View Article][PubMed]
    [Google Scholar]
  52. Lassen KG, Ramyar KX, Bailey JR, Zhou Y, Siliciano RF. Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells. PLoS Pathog 2006; 2:e68 [View Article][PubMed]
    [Google Scholar]
  53. Huang J, Wang F, Argyris E, Chen K, Liang Z et al. Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med 2007; 13:1241–1247 [View Article][PubMed]
    [Google Scholar]
  54. Zhu Y, Chen G, Lv F, Wang X, Ji X et al. Zinc-finger antiviral protein inhibits HIV-1 infection by selectively targeting multiply spliced viral mRNAs for degradation. Proc Natl Acad Sci USA 2011; 108:15834–15839 [View Article][PubMed]
    [Google Scholar]
  55. Harwig A, das AT, Berkhout B. Retroviral microRNAs. Curr Opin Virol 2014; 7:47–54 [View Article][PubMed]
    [Google Scholar]
  56. Chen AK, Sengupta P, Waki K, van Engelenburg SB, Ochiya T et al. MicroRNA binding to the HIV-1 gag protein inhibits gag assembly and virus production. Proc Natl Acad Sci USA 2014; 111:E2676E2683 [View Article][PubMed]
    [Google Scholar]
  57. Triboulet R, Mari B, Lin YL, Chable-Bessia C, Bennasser Y et al. Suppression of microRNA-silencing pathway by HIV-1 during virus replication. Science 2007; 315:1579–1582 [View Article][PubMed]
    [Google Scholar]
  58. Singhal R, Bard JE, Nowak NJ, Buck MJ, Kandel ES. FOXO1 regulates expression of a microRNA cluster on X chromosome. Aging 2013; 5:347–356 [View Article][PubMed]
    [Google Scholar]
  59. Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 2006; 20:515–524 [View Article][PubMed]
    [Google Scholar]
  60. Denli AM, Hannon GJ. RNAi: an ever-growing puzzle. Trends Biochem Sci 2003; 28:196–201 [View Article][PubMed]
    [Google Scholar]
  61. Ji X. The mechanism of RNase III action: how dicer dices. Curr Top Microbiol Immunol 2008; 320:99–116[PubMed]
    [Google Scholar]
  62. Saunders LR, Barber GN. The dsRNA binding protein family: critical roles, diverse cellular functions. Faseb J 2003; 17:961–983 [View Article][PubMed]
    [Google Scholar]
  63. Chable-Bessia C, Meziane O, Latreille D, Triboulet R, Zamborlini A et al. Suppression of HIV-1 replication by microRNA effectors. Retrovirology 2009; 6:26 [View Article][PubMed]
    [Google Scholar]
  64. Kilchert C, Wittmann S, Vasiljeva L. The regulation and functions of the nuclear RNA exosome complex. Nat Rev Mol Cell Biol 2016; 17:227–239 [View Article][PubMed]
    [Google Scholar]
  65. Rigby RE, Rehwinkel J. RNA degradation in antiviral immunity and autoimmunity. Trends Immunol 2015; 36:179–188 [View Article][PubMed]
    [Google Scholar]
  66. Guo X, Ma J, Sun J, Gao G. The zinc-finger antiviral protein recruits the RNA processing exosome to degrade the target mRNA. Proc Natl Acad Sci USA 2007; 104:151–156 [View Article][PubMed]
    [Google Scholar]
  67. Schilders G, Pruijn GJ. Biochemical studies of the mammalian exosome with intact cells. Methods Enzymol 2008; 448:211–226 [View Article][PubMed]
    [Google Scholar]
  68. Fabre S, Lang V, Harriague J, Jobart A, Unterman TG et al. Stable activation of phosphatidylinositol 3-kinase in the T cell immunological synapse stimulates Akt signaling to FoxO1 nuclear exclusion and cell growth control. J Immunol 2005; 174:4161–4171 [View Article][PubMed]
    [Google Scholar]
  69. Sadowski I, Lourenco P, Malcolm T. Factors controlling chromatin organization and nucleosome positioning for establishment and maintenance of HIV latency. Curr HIV Res 2008; 6:286–295 [View Article][PubMed]
    [Google Scholar]
  70. Trinité B, Chan CN, Lee CS, Mahajan S, Luo Y et al. Suppression of Foxo1 activity and down-modulation of CD62L (L-selectin) in HIV-1 infected resting CD4 T cells. PLoS One 2014; 9:e110719 [View Article][PubMed]
    [Google Scholar]
  71. Cantaluppi V, Biancone L, Boccellino M, Doublier S, Benelli R et al. HIV type 1 Tat protein is a survival factor for kaposi's sarcoma and endothelial cells. AIDS Res Hum Retroviruses 2001; 17:965–976 [View Article][PubMed]
    [Google Scholar]
  72. Deregibus MC, Cantaluppi V, Doublier S, Brizzi MF, Deambrosis I et al. HIV-1-Tat protein activates phosphatidylinositol 3-kinase/ AKT-dependent survival pathways in Kaposi's sarcoma cells. J Biol Chem 2002; 277:25195–25202 [View Article][PubMed]
    [Google Scholar]
  73. Muthumani K, Shedlock DJ, Choo DK, Fagone P, Kawalekar OU et al. HIV-mediated phosphatidylinositol 3-kinase/serine-threonine kinase activation in APCs leads to programmed death-1 ligand upregulation and suppression of HIV-specific CD8 T cells. J Immunol 2011; 187:2932–2943 [View Article][PubMed]
    [Google Scholar]
  74. Bennasser Y, Le SY, Benkirane M, Jeang KT. Evidence that HIV-1 encodes an siRNA and a suppressor of RNA silencing. Immunity 2005; 22:607–619 [View Article][PubMed]
    [Google Scholar]
  75. Karki S, Li MM, Schoggins JW, Tian S, Rice CM et al. Multiple interferon stimulated genes synergize with the zinc finger antiviral protein to mediate anti-alphavirus activity. PLoS One 2012; 7:e37398 [View Article][PubMed]
    [Google Scholar]
  76. Bouwman RD, Palser A, Parry CM, Coulter E, Rasaiyaah J et al. Human immunodeficiency virus Tat associates with a specific set of cellular RNAs. Retrovirology 2014; 11:53 [View Article][PubMed]
    [Google Scholar]
  77. Espert L, Degols G, Gongora C, Blondel D, Williams BR et al. ISG20, a new interferon-induced RNase specific for single-stranded RNA, defines an alternative antiviral pathway against RNA genomic viruses. J Biol Chem 2003; 278:16151–16158 [View Article][PubMed]
    [Google Scholar]
  78. Espert L, Degols G, Lin YL, Vincent T, Benkirane M et al. Interferon-induced exonuclease ISG20 exhibits an antiviral activity against human immunodeficiency virus type 1. J Gen Virol 2005; 86:2221–2229 [View Article][PubMed]
    [Google Scholar]
  79. Nguyen LH, Espert L, Mechti N, Wilson DM. The human interferon- and estrogen-regulated ISG20/HEM45 gene product degrades single-stranded RNA and DNA in vitro. Biochemistry 2001; 40:7174–7179 [View Article][PubMed]
    [Google Scholar]
  80. Xu H, Lei Y, Zhong S, Peng FY, Zhou Z et al. [Antiviral activities of ISG20 against hepatitis C virus]. Zhonghua Gan Zang Bing Za Zhi 2013; 21:33–37[PubMed]
    [Google Scholar]
  81. Zhou Z, Wang N, Woodson SE, Dong Q, Wang J et al. Antiviral activities of ISG20 in positive-strand RNA virus infections. Virology 2011; 409:175–188 [View Article][PubMed]
    [Google Scholar]
  82. Espert L, Eldin P, Gongora C, Bayard B, Harper F et al. The exonuclease ISG20 mainly localizes in the nucleolus and the Cajal (Coiled) bodies and is associated with nuclear SMN protein-containing complexes. J Cell Biochem 2006; 98:1320–1333 [View Article][PubMed]
    [Google Scholar]
  83. Houseley J, Tollervey D. The many pathways of RNA degradation. Cell 2009; 136:763–776 [View Article][PubMed]
    [Google Scholar]
  84. Tang ED, Nuñez G, Barr FG, Guan KL. Negative regulation of the forkhead transcription factor FKHR by Akt. J Biol Chem 1999; 274:16741–16746 [View Article][PubMed]
    [Google Scholar]
  85. Cujec TP, Okamoto H, Fujinaga K, Meyer J, Chamberlin H et al. The HIV transactivator TAT binds to the CDK-activating kinase and activates the phosphorylation of the carboxy-terminal domain of RNA polymerase II. Genes Dev 1997; 11:2645–2657 [View Article][PubMed]
    [Google Scholar]
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