Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes

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The advent of antiretroviral therapy has greatly improved the prognosis for HIV-infected individuals with access to care. However, current therapies are unable to cure infection, committing treated individuals to a lifetime of medication with significant economic burden. Furthermore, it has become clear that antiretroviral therapy does not completely restore health, leaving treated HIV-infected individuals at increased risk of cardiovascular disease, neurological disorders, and other health issues. Thus, there is a need to develop therapies capable of curing HIV infection. It is thought that, to be successful, curative strategies will need to combine a means to flush the virus out of the latently-infected cells in which it hides, with a means to kill these unmasked targets. A front-running approach proposes to use a class of drugs called histone deacetylase inhibitors (HDACis) as flushing agents, with cytotoxic T-lymphocytes (CTL, or killer T-cells) to purge viral reservoirs. Here, we uncover an unexpected negative interaction between these two agents, whereby HDACis suppress the ability of CTL to kill HIV-infected cells. This interaction has the potential to limit the effectiveness of combining CTL with HDACis in flush and kill approaches to HIV eradication, and should be considered in the prioritization and optimization of potential curative strategies.

Vyšlo v časopise: Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes. PLoS Pathog 10(8): e32767. doi:10.1371/journal.ppat.1004287
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004287

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Zdroje

1. DeeksSG (2011) HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med 62: 141–155.

2. DeeksSG, LewinSR, HavlirDV (2013) The end of AIDS: HIV infection as a chronic disease. Lancet 382: 1525–1533.

3. ChunTW, StuyverL, MizellSB, EhlerLA, MicanJA, et al. (1997) Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A 94: 13193–13197.

4. FinziD, HermankovaM, PiersonT, CarruthLM, BuckC, et al. (1997) Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278: 1295–1300.

5. WongJK, HezarehM, GunthardHF, HavlirDV, IgnacioCC, et al. (1997) Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278: 1291–1295.

6. FinziD, BlanksonJ, SilicianoJD, MargolickJB, ChadwickK, et al. (1999) Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 5: 512–517.

7. ChomontN, El-FarM, AncutaP, TrautmannL, ProcopioFA, et al. (2009) HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 15: 893–900.

8. BuzonMJ, MassanellaM, LlibreJM, EsteveA, DahlV, et al. (2010) HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med 16: 460–465.

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

10. 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.

11. RasmussenTA, Schmeltz SogaardO, BrinkmannC, WightmanF, LewinSR, et al. (2013) Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. Hum Vaccin Immunother 9: 993–1001.

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

13. 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.

14. LicciardiPV, KaragiannisTC (2012) Regulation of immune responses by histone deacetylase inhibitors. ISRN Hematol 2012: 690901.

15. AkimovaT, BeierUH, LiuY, WangL, HancockWW (2012) Histone/protein deacetylases and T-cell immune responses. Blood 119: 2443–2451.

16. BosisioD, VulcanoM, Del PreteA, SironiM, SalviV, et al. (2008) Blocking TH17-polarizing cytokines by histone deacetylase inhibitors in vitro and in vivo. J Leukoc Biol 84: 1540–1548.

17. GlaubenR, BatraA, FedkeI, ZeitzM, LehrHA, et al. (2006) Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J Immunol 176: 5015–5022.

18. LeoniF, ZalianiA, BertoliniG, PorroG, PaganiP, et al. (2002) The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc Natl Acad Sci U S A 99: 2995–3000.

19. MishraN, ReillyCM, BrownDR, RuizP, GilkesonGS (2003) Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. J Clin Invest 111: 539–552.

20. ReddyP, MaedaY, HotaryK, LiuC, ReznikovLL, et al. (2004) Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. Proc Natl Acad Sci U S A 101: 3921–3926.

21. ShiZJ, OuyangDY, ZhuJS, XuLH, HeXH (2012) Histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits anti-inflammatory activities through induction of mitochondrial damage and apoptosis in activated lymphocytes. Int Immunopharmacol 12: 580–587.

22. BrogdonJL, XuY, SzaboSJ, AnS, BuxtonF, et al. (2007) Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function. Blood 109: 1123–1130.

23. GeZ, DaY, XueZ, ZhangK, ZhuangH, et al. (2013) Vorinostat, a histone deacetylase inhibitor, suppresses dendritic cell function and ameliorates experimental autoimmune encephalomyelitis. Exp Neurol 241: 56–66.

24. Kelly-SellMJ, KimYH, StrausS, BenoitB, HarrisonC, et al. (2012) The histone deacetylase inhibitor, romidepsin, suppresses cellular immune functions of cutaneous T-cell lymphoma patients. Am J Hematol 87: 354–360.

25. MoreiraJM, ScheipersP, SorensenP (2003) The histone deacetylase inhibitor Trichostatin A modulates CD4+ T cell responses. BMC Cancer 3: 30.

26. WangB, MorinobuA, HoriuchiM, LiuJ, KumagaiS (2008) Butyrate inhibits functional differentiation of human monocyte-derived dendritic cells. Cell Immunol 253: 54–58.

27. BohmigGA, KriegerPM, SaemannMD, WenhardtC, PohankaE, et al. (1997) n-butyrate downregulates the stimulatory function of peripheral blood-derived antigen-presenting cells: a potential mechanism for modulating T-cell responses by short-chain fatty acids. Immunology 92: 234–243.

28. CameloS, IglesiasAH, HwangD, DueB, RyuH, et al. (2005) Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol 164: 10–21.

29. DowdellKC, PesnicakL, HoffmannV, SteadmanK, RemaleyAT, et al. (2009) Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, diminishes lymphoproliferation in the Fas -deficient MRL/lpr(−/−) murine model of autoimmune lymphoproliferative syndrome (ALPS). Exp Hematol 37: 487–494.

30. GarciaBA, BusbySA, ShabanowitzJ, HuntDF, MishraN (2005) Resetting the epigenetic histone code in the MRL-lpr/lpr mouse model of lupus by histone deacetylase inhibition. J Proteome Res 4: 2032–2042.

31. LarsenL, TonnesenM, RonnSG, StorlingJ, JorgensenS, et al. (2007) Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells. Diabetologia 50: 779–789.

32. ReddyP, SunY, ToubaiT, Duran-StruuckR, ClouthierSG, et al. (2008) Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. J Clin Invest 118: 2562–2573.

33. WangD, IclozanC, LiuC, XiaC, AnasettiC, et al. (2012) LBH589 enhances T cell activation in vivo and accelerates graft-versus-host disease in mice. Biol Blood Marrow Transplant 18: 1182–1190 e1181.

34. BridleBW, ChenL, LemayCG, DialloJS, PolJ, et al. (2013) HDAC inhibition suppresses primary immune responses, enhances secondary immune responses, and abrogates autoimmunity during tumor immunotherapy. Mol Ther 21: 887–894.

35. KhanN, JeffersM, KumarS, HackettC, BoldogF, et al. (2008) Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem J 409: 581–589.

36. LiuT, KuljacaS, TeeA, MarshallGM (2006) Histone deacetylase inhibitors: multifunctional anticancer agents. Cancer Treat Rev 32: 157–165.

37. MarksPA, RichonVM, MillerT, KellyWK (2004) Histone deacetylase inhibitors. Adv Cancer Res 91: 137–168.

38. LindemannRK, GabrielliB, JohnstoneRW (2004) Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle 3: 779–788.

39. MayoMW, DenlingerCE, BroadRM, YeungF, ReillyET, et al. (2003) Ineffectiveness of histone deacetylase inhibitors to induce apoptosis involves the transcriptional activation of NF-kappa B through the Akt pathway. J Biol Chem 278: 18980–18989.

40. JohnstoneRW (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1: 287–299.

41. TaoR, de ZoetenEF, OzkaynakE, ChenC, WangL, et al. (2007) Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 13: 1299–1307.

42. CocchiF, DeVicoAL, Garzino-DemoA, AryaSK, GalloRC, et al. (1995) Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 270: 1811–1815.

43. BeierUH, AkimovaT, LiuY, WangL, HancockWW (2011) Histone/protein deacetylases control Foxp3 expression and the heat shock response of T-regulatory cells. Curr Opin Immunol 23: 670–678.

44. ClouseKA, PowellD, WashingtonI, PoliG, StrebelK, et al. (1989) Monokine regulation of human immunodeficiency virus-1 expression in a chronically infected human T cell clone. J Immunol 142: 431–438.

45. FoleyMH, ForcierT, McAndrewE, GonzalezM, ChenH, et al. (2014) High avidity CD8+ T cells efficiently eliminate motile hiv-infected targets and execute a locally focused program of anti-viral function. PLoS One 9: e87873.

46. RothsteinTL, MageM, JonesG, McHughLL (1978) Cytotoxic T lymphocyte sequential killing of immobilized allogeneic tumor target cells measured by time-lapse microcinematography. J Immunol 121: 1652–1656.

47. SandersonCJ (1976) The mechanism of T cell mediated cytotoxicity. II. Morphological studies of cell death by time-lapse microcinematography. Proc R Soc Lond B Biol Sci 192: 241–255.

48. MatterA (1979) Microcinematographic and electron microscopic analysis of target cell lysis induced by cytotoxic T lymphocytes. Immunology 36: 179–190.

49. Corporation C (2013) Istodax Package Insert.

50. ZhuX, MarcusWD, XuW, LeeHI, HanK, et al. (2009) Novel human interleukin-15 agonists. J Immunol 183: 3598–3607.

51. HanKP, ZhuX, LiuB, JengE, KongL, et al. (2011) IL-15:IL-15 receptor alpha superagonist complex: high-level co-expression in recombinant mammalian cells, purification and characterization. Cytokine 56: 804–810.

52. JennesW, KestensL, NixonDF, ShacklettBL (2002) Enhanced ELISPOT detection of antigen-specific T cell responses from cryopreserved specimens with addition of both IL-7 and IL-15–the Amplispot assay. J Immunol Methods 270: 99–108.

53. StrengellM, MatikainenS, SirenJ, LehtonenA, FosterD, et al. (2003) IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells. J Immunol 170: 5464–5469.

54. ShapiroGI, FrankR, DandamudiUB, HengelageT, ZhaoL, et al. (2012) The effect of food on the bioavailability of panobinostat, an orally active pan-histone deacetylase inhibitor, in patients with advanced cancer. Cancer Chemother Pharmacol 69: 555–562.

55. WeiDG, ChiangV, FyneE, BalakrishnanM, BarnesT, et al. (2014) Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing. PLoS Pathog 10: e1004071.

56. RubinEH, AgrawalNG, FriedmanEJ, ScottP, MazinaKE, et al. (2006) A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. Clin Cancer Res 12: 7039–7045.

57. MejiaEJ, LoveridgeST, StepanG, TsaiA, JonesGS, et al. (2014) Study of Marine Natural Products Including Resorcyclic Acid Lactones from Humicola fuscoatra That Reactivate Latent HIV-1 Expression in an in Vitro Model of Central Memory CD4+ T Cells. J Nat Prod 77: 618–24..

58. JonesRB, YueFY, GuXX, HunterDV, MujibS, et al. (2009) Human immunodeficiency virus type 1 escapes from interleukin-2-producing CD4+ T-cell responses without high-frequency fixation of mutations. J Virol 83: 8722–8732.

59. StreeckH, FrahmN, WalkerBD (2009) The role of IFN-gamma Elispot assay in HIV vaccine research. Nat Protoc 4: 461–469.

60. WalkerBD, FlexnerC, Birch-LimbergerK, FisherL, ParadisTJ, et al. (1989) Long-term culture and fine specificity of human cytotoxic T-lymphocyte clones reactive with human immunodeficiency virus type 1. Proc Natl Acad Sci U S A 86: 9514–9518.

61. JonesRB, GarrisonKE, MujibS, MihajlovicV, AidarusN, et al. (2012) HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates. J Clin Invest 122: 4473–4489.

62. SachaJB, WatkinsDI (2010) Synchronous infection of SIV and HIV in vitro for virology, immunology and vaccine-related studies. Nat Protoc 5: 239–246.