Activation of HIV-1 from Latent Infection via Synergy of RUNX1 Inhibitor Ro5-3335 and SAHA

English version České info

Since it was first discovered in the early 1980s, Human Immunodeficiency Virus 1 (HIV-1), the causative agent of Acquired Immunodeficiency Syndrome (AIDS), has been the focus of intense research. In untreated individuals, the number of CD4+ T-cells in the blood slowly drops over time and the patient eventually succumbs to an opportunistic infection. Although current therapies are capable of managing the virus; they do not represent a true cure. As a retrovirus, HIV-1 incorporates itself into the host genome and survives in the long-lived population of memory T-cells found in the human host. In this study, we examine the roll of a T-cell specific transcription factor (RUNX1) in the control of HIV-1 replication. Through various molecular studies, we show that RUNX1 represses HIV-1 replication in T-cells. By examining samples from patients with HIV-1, we are able to show a negative correlation between viral replication and RUNX1 expression. Finally, we show that an inhibitor of RUNX1 synergizes with Vorinostat, a current lead compound in the quest to re-active HIV-1 and purge the latent pool.

Vyšlo v časopise: Activation of HIV-1 from Latent Infection via Synergy of RUNX1 Inhibitor Ro5-3335 and SAHA. PLoS Pathog 10(3): e32767. doi:10.1371/journal.ppat.1003997
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003997

Souhrn

Zdroje

1. GreeneWC, PeterlinBM (2002) Charting HIV's remarkable voyage through the cell: Basic science as a passport to future therapy. Nat Med 8: 673–680.

2. BerkhoutB, JeangKT (1989) trans activation of human immunodeficiency virus type 1 is sequence specific for both the single-stranded bulge and loop of the trans-acting-responsive hairpin: a quantitative analysis. J Virol 63: 5501–5504.

3. BerkhoutB, SilvermanRH, JeangKT (1989) Tat trans-activates the human immunodeficiency virus through a nascent RNA target. Cell 59: 273–282.

4. YedavalliVS, BenkiraneM, JeangKT (2003) Tat and trans-activation-responsive (TAR) RNA-independent induction of HIV-1 long terminal repeat by human and murine cyclin T1 requires Sp1. J Biol Chem 278: 6404–6410.

5. BradyJ, KashanchiF (2005) Tat gets the "green" light on transcription initiation. Retrovirology 2: 69.

6. HakreS, ChavezL, ShirakawaK, VerdinE (2014) Epigenetic regulation of HIV latency. Curr Opin HIV AIDS 6: 19–24.

7. KarnJ (2011) The molecular biology of HIV latency: breaking and restoring the Tat-dependent transcriptional circuit. Curr Opin HIV AIDS 6: 4–11.

8. MargolisDM (2010) Mechanisms of HIV latency: an emerging picture of complexity. Curr HIV/AIDS Rep 7: 37–43.

9. BlythK, CameronER, NeilJC (2005) The RUNX genes: gain or loss of function in cancer. Nat Rev Cancer 5: 376–387.

10. LiX, DeckerM, WestendorfJJ (2010) TEThered to Runx: novel binding partners for runx factors. Blood Cells Mol Dis 45: 82–85.

11. AdyaN, StacyT, SpeckNA, LiuPP (1998) The leukemic protein core binding factor beta (CBFbeta)-smooth-muscle myosin heavy chain sequesters CBFalpha2 into cytoskeletal filaments and aggregates. Mol Cell Biol 18: 7432–7443.

12. TaniuchiI, OsatoM, EgawaT, SunshineMJ, BaeSC, et al. (2002) Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell 111: 621–633.

13. WongWF, KohuK, ChibaT, SatoT, SatakeM (2011) Interplay of transcription factors in T-cell differentiation and function: the role of Runx. Immunology 132: 157–164.

14. WongWF, KurokawaM, SatakeM, KohuK (2011) Down-regulation of Runx1 expression by TCR signal involves an autoregulatory mechanism and contributes to IL-2 production. J Biol Chem 286: 11110–11118.

15. DjureticIM, Cruz-GuillotyF, RaoA (2009) Regulation of gene expression in peripheral T cells by Runx transcription factors. Adv Immunol 104: 1–23.

16. BaeSC, LeeYH (2006) Phosphorylation, acetylation and ubiquitination: the molecular basis of RUNX regulation. Gene 366: 58–66.

17. WeeHJ, VoonDC, BaeSC, ItoY (2008) PEBP2-beta/CBF-beta-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis. Blood 112: 3777–3787.

18. TaniuchiI, LittmanDR (2004) Epigenetic gene silencing by Runx proteins. Oncogene 23: 4341–4345.

19. DurstKL, HiebertSW (2004) Role of RUNX family members in transcriptional repression and gene silencing. Oncogene 23: 4220–4224.

20. Hultquist JF, McDougle RM, Anderson BD, Harris RS (2012) HIV Type 1 Viral Infectivity Factor and the RUNX Transcription Factors Interact with Core Binding Factor beta on Genetically Distinct Surfaces. AIDS Res Hum Retroviruses.

21. JagerS, KimDY, HultquistJF, ShindoK, LaRueRS, et al. (2012) Vif hijacks CBF-beta to degrade APOBEC3G and promote HIV-1 infection. Nature 481: 371–375.

22. ZhangW, DuJ, EvansSL, YuY, YuXF (2012) T-cell differentiation factor CBF-beta regulates HIV-1 Vif-mediated evasion of host restriction. Nature 481: 376–379.

23. Kim DY, Kwon E, Hartley PD, Crosby DC, Mann S, et al.. (2013) CBFbeta Stabilizes HIV Vif to Counteract APOBEC3 at the Expense of RUNX1 Target Gene Expression. Mol Cell.

24. CunninghamL, FinckbeinerS, HydeRK, SouthallN, MaruganJ, et al. (2012) Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1-CBFbeta interaction. Proc Natl Acad Sci U S A 109: 14592–14597.

25. LevanonD, GronerY (2004) Structure and regulated expression of mammalian RUNX genes. Oncogene 23: 4211–4219.

26. HuangG, ShigesadaK, WeeHJ, LiuPP, OsatoM, et al. (2004) Molecular basis for a dominant inactivation of RUNX1/AML1 by the leukemogenic inversion 16 chimera. Blood 103: 3200–3207.

27. YamashitaN, OsatoM, HuangL, YanagidaM, KoganSC, et al. (2005) Haploinsufficiency of Runx1/AML1 promotes myeloid features and leukaemogenesis in BXH2 mice. Br J Haematol 131: 495–507.

28. PresnellSR, ZhangL, RamiloCA, ChanHW, LutzCT (2006) Functional redundancy of transcription factor-binding sites in the killer cell Ig-like receptor (KIR) gene promoter. Int Immunol 18: 1221–1232.

29. Schug J (2008) Using TESS to predict transcription factor binding sites in DNA sequence. Curr Protoc Bioinformatics Chapter 2: Unit 2 6.

30. CrooksGE, HonG, ChandoniaJM, BrennerSE (2004) WebLogo: a sequence logo generator. Genome Res 14: 1188–1190.

31. SorensenKD, Quintanilla-MartinezL, KunderS, SchmidtJ, PedersenFS (2004) Mutation of all Runx (AML1/core) sites in the enhancer of T-lymphomagenic SL3-3 murine leukemia virus unmasks a significant potential for myeloid leukemia induction and favors enhancer evolution toward induction of other disease patterns. J Virol 78: 13216–13231.

32. SheehyAM, GaddisNC, ChoiJD, MalimMH (2002) Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418: 646–650.

33. WangJ, ReuschelEL, ShackelfordJM, JeangL, ShiversDK, et al. (2011) HIV-1 Vif promotes the G(1)- to S-phase cell-cycle transition. Blood 117: 1260–1269.

34. ChallenGA, GoodellMA (2010) Runx1 isoforms show differential expression patterns during hematopoietic development but have similar functional effects in adult hematopoietic stem cells. Exp Hematol 38: 403–416.

35. WongWF, NakazatoM, WatanabeT, KohuK, OgataT, et al. (2010) Over-expression of Runx1 transcription factor impairs the development of thymocytes from the double-negative to double-positive stages. Immunology 130: 243–253.

36. JordanA, BisgroveD, VerdinE (2003) HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J 22: 1868–1877.

37. ArchinNM, EspesethA, ParkerD, CheemaM, HazudaD, et al. (2009) Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid. AIDS Res Hum Retroviruses 25: 207–212.

38. CollinsA, LittmanDR, TaniuchiI (2009) RUNX proteins in transcription factor networks that regulate T-cell lineage choice. Nat Rev Immunol 9: 106–115.

39. EgawaT (2009) Runx and ThPOK: a balancing act to regulate thymocyte lineage commitment. J Cell Biochem 107: 1037–1045.

40. ContrerasX, SchwenekerM, ChenCS, McCuneJM, DeeksSG, et al. (2009) Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J Biol Chem 284: 6782–6789.

41. EdelsteinLC, Micheva-VitevaS, PhelanBD, DoughertyJP (2009) Short communication: activation of latent HIV type 1 gene expression by suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor approved for use to treat cutaneous T cell lymphoma. AIDS Res Hum Retroviruses 25: 883–887.

42. WightmanF, EllenbergP, ChurchillM, LewinSR (2012) HDAC inhibitors in HIV. Immunol Cell Biol 90: 47–54.

43. ArchinNM, LibertyAL, KashubaAD, ChoudharySK, KurucJD, et al. (2012) Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 487: 482–485.

44. ShanL, DengK, ShroffNS, DurandCM, RabiSA, et al. (2012) Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity 36: 491–501.

45. HsuMC, SchuttAD, HollyM, SliceLW, ShermanMI, et al. (1991) Inhibition of HIV replication in acute and chronic infections in vitro by a Tat antagonist. Science 254: 1799–1802.

46. MeiHY, MackDP, GalanAA, HalimNS, HeldsingerA, et al. (1997) Discovery of selective, small-molecule inhibitors of RNA complexes—I. The Tat protein/TAR RNA complexes required for HIV-1 transcription. Bioorg Med Chem 5: 1173–1184.

47. DunneAL, SiregarH, MillsJ, CroweSM (1994) HIV replication in chronically infected macrophages is not inhibited by the Tat inhibitors Ro-5-3335 and Ro-24-7429. J Leukoc Biol 56: 369–373.

48. CupelliLA, HsuMC (1995) The human immunodeficiency virus type 1 Tat antagonist, Ro 5-3335, predominantly inhibits transcription initiation from the viral promoter. J Virol 69: 2640–2643.

49. HaubrichRH, FlexnerC, LedermanMM, HirschM, PettinelliCP, et al. (1995) A randomized trial of the activity and safety of Ro 24-7429 (Tat antagonist) versus nucleoside for human immunodeficiency virus infection. The AIDS Clinical Trials Group 213 Team. J Infect Dis 172: 1246–1252.

50. CohenMMJr (2009) Perspectives on RUNX genes: an update. Am J Med Genet A 149A: 2629–2646.

51. Collins A, Hewitt SL, Chaumeil J, Sellars M, Micsinai M, et al. RUNX Transcription Factor-Mediated Association of Cd4 and Cd8 Enables Coordinate Gene Regulation. Immunity 34: 303–314.

52. WuC, OrozcoC, BoyerJ, LegliseM, GoodaleJ, et al. (2009) BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol 10: R130.