Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb Activation

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Stable latent viral reservoirs in HIV infected individuals are rapidly reactivated following the interruption of anti-retroviral therapy (ART). Despite an early initiation of ART, viral reservoirs are established and persist as demonstrated in the case of the Mississippi baby and from recent studies of the SIV model of AIDS. Therefore, new strategies are needed for the eradication of the latent HIV reservoirs. We found that ingenol-3-angelate (PEP005), a member of the new class of anti-cancer ingenol compounds, effectively reactivated HIV from latency in primary CD4+ T cells from HIV infected individuals receiving ART. Importantly, a combination of PEP005 and JQ1, a p-TEFb agonist, reactivated HIV from latency at level on average 7.5-fold higher compared to PEP005 alone. The potency of synergistic effects of PEP005 and JQ1 provide novel opportunities for advancing HIV eradication strategies in the future. In summary, ingenols represent a new group of lead compounds for combating HIV latency.

Vyšlo v časopise: Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb Activation. PLoS Pathog 11(7): e32767. doi:10.1371/journal.ppat.1005066
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005066

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Zdroje

1. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, et al. (1997) Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278: 1295–1300. 9360927

2. Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, et al. (2003) Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 9: 727–728. 12754504

3. Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, et al. (1997) Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278: 1291–1295. 9360926

4. Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, 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. 9371822

5. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, et al. (2009) HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 15: 893–900. doi: 10.1038/nm.1972 19543283

6. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, et al. (2009) The challenge of finding a cure for HIV infection. Science 323: 1304–1307. doi: 10.1126/science.1165706 19265012

7. Lerner P, Guadalupe M, Donovan R, Hung J, Flamm J, et al. (2011) The gut mucosal viral reservoir in HIV-infected patients is not the major source of rebound plasma viremia following interruption of highly active antiretroviral therapy. J Virol 85: 4772–4782. doi: 10.1128/JVI.02409-10 21345945

8. Guadalupe M, Reay E, Sankaran S, Prindiville T, Flamm J, et al. (2003) Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol 77: 11708–11717. 14557656

9. Giacomet V, Trabattoni D, Zanchetta N, Biasin M, Gismondo M, et al. (2014) No cure of HIV infection in a child despite early treatment and apparent viral clearance. Lancet 384: 1320. doi: 10.1016/S0140-6736(14)61405-7 25283573

10. Hirao LA, Grishina I, Bourry O, Hu WK, Somrit M, et al. (2014) Early mucosal sensing of SIV infection by paneth cells induces IL-1beta production and initiates gut epithelial disruption. PLoS Pathog 10: e1004311. doi: 10.1371/journal.ppat.1004311 25166758

11. Whitney JB, Hill AL, Sanisetty S, Penaloza-MacMaster P, Liu J, et al. (2014) Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature.

12. Persaud D, Gay H, Ziemniak C, Chen YH, Piatak M Jr., et al. (2013) Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med 369: 1828–1835. doi: 10.1056/NEJMoa1302976 24152233

13. Shalit P (2014) Management of dyslipidemia in patients with human immunodeficiency virus. Rev Cardiovasc Med 15 Suppl 1: S38–46. 24987862

14. Freitas P, Carvalho D, Santos AC, Madureira AJ, Martinez E, et al. (2014) Adipokines, hormones related to body composition, and insulin resistance in HIV fat redistribution syndrome. BMC Infect Dis 14: 347. doi: 10.1186/1471-2334-14-347 24958357

15. Nasi M, Pinti M, De Biasi S, Gibellini L, Ferraro D, et al. (2014) Aging with HIV infection: A journey to the center of inflammAIDS, immunosenescence and neuroHIV. Immunol Lett.

16. Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, et al. (2012) Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 487: 482–485. doi: 10.1038/nature11286 22837004

17. Elliott JH, Wightman F, Solomon A, Ghneim K, Ahlers J, et al. (2014) Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog 10: e1004473. doi: 10.1371/journal.ppat.1004473 25393648

18. Rasmussen TA, Schmeltz Sogaard O, Brinkmann C, Wightman F, Lewin SR, 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. doi: 10.4161/hv.23800 23370291

19. Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, et al. (2012) Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity 36: 491–501. doi: 10.1016/j.immuni.2012.01.014 22406268

20. Spina CA, Anderson J, Archin NM, Bosque A, Chan J, et al. (2013) An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathog 9: e1003834. doi: 10.1371/journal.ppat.1003834 24385908

21. Jiang G, Espeseth A, Hazuda DJ, Margolis DM (2007) c-Myc and Sp1 contribute to proviral latency by recruiting histone deacetylase 1 to the human immunodeficiency virus type 1 promoter. J Virol 81: 10914–10923. 17670825

22. Jiang G, Dandekar S (2014) Targeting NF-kappaB signaling with protein kinase C agonists as an emerging strategy for combating HIV latency. AIDS Res Hum Retroviruses.

23. Beans EJ, Fournogerakis D, Gauntlett C, Heumann LV, Kramer R, et al. (2013) Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo. Proc Natl Acad Sci U S A 110: 11698–11703. doi: 10.1073/pnas.1302634110 23812750

24. Jiang G, Mendes EA, Kaiser P, Sankaran-Walters S, Tang Y, et al. (2014) Reactivation of HIV latency by a newly modified Ingenol derivative via protein kinase Cdelta-NF-kappaB signaling. AIDS.

25. Huang L, Ho P, Yu J, Zhu L, Lee KH, et al. (2011) Picomolar dichotomous activity of gnidimacrin against HIV-1. PLoS One 6: e26677. doi: 10.1371/journal.pone.0026677 22039528

26. Bullen CK, Laird GM, Durand CM, Siliciano JD, Siliciano RF (2014) New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med 20: 425–429. doi: 10.1038/nm.3489 24658076

27. Abreu CM, Price SL, Shirk EN, Cunha RD, Pianowski LF, et al. (2014) Dual role of novel ingenol derivatives from Euphorbia tirucalli in HIV replication: inhibition of de novo infection and activation of viral LTR. PLoS One 9: e97257. doi: 10.1371/journal.pone.0097257 24827152

28. Pandelo Jose D, Bartholomeeusen K, da Cunha RD, Abreu CM, Glinski J, et al. (2014) Reactivation of latent HIV-1 by new semi-synthetic ingenol esters. Virology 462-463C: 328–339.

29. Fidler B, Goldberg T (2014) Ingenol mebutate gel (picato): a novel agent for the treatment of actinic keratoses. P T 39: 40–46. 24672213

30. Warrilow D, Gardner J, Darnell GA, Suhrbier A, Harrich D (2006) HIV type 1 inhibition by protein kinase C modulatory compounds. AIDS Res Hum Retroviruses 22: 854–864. 16989610

31. Emiliani S, Fischle W, Ott M, Van Lint C, Amella CA, et al. (1998) Mutations in the tat gene are responsible for human immunodeficiency virus type 1 postintegration latency in the U1 cell line. J Virol 72: 1666–1670. 9445075

32. Jordan A, Bisgrove D, Verdin E (2003) HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J 22: 1868–1877. 12682019

33. Kumar AM, Borodowsky I, Fernandez B, Gonzalez L, Kumar M (2007) Human immunodeficiency virus type 1 RNA Levels in different regions of human brain: quantification using real-time reverse transcriptase-polymerase chain reaction. J Neurovirol 13: 210–224. 17613711

34. Shan L, Rabi SA, Laird GM, Eisele EE, Zhang H, et al. (2013) A novel PCR assay for quantification of HIV-1 RNA. J Virol 87: 6521–6525. doi: 10.1128/JVI.00006-13 23536672

35. Laird GM, Bullen CK, Rosenbloom DI, Martin AR, Hill AL, et al. (2015) Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations. J Clin Invest.

36. Bliss CI (1939) The toxicity of poisons applied jointly. Annals of Applied Biology 26: 585–615.

37. Jiang G, Sancar A (2006) Recruitment of DNA damage checkpoint proteins to damage in transcribed and nontranscribed sequences. Mol Cell Biol 26: 39–49. 16354678

38. Tang Y, George A, Nouvet F, Sweet S, Emeagwali N, et al. (2014) Infection of female primary lower genital tract epithelial cells after natural pseudotyping of HIV-1: possible implications for sexual transmission of HIV-1. PLoS One 9: e101367. doi: 10.1371/journal.pone.0101367 25010677

39. Lavigne M, Eskeland R, Azebi S, Saint-Andre V, Jang SM, et al. (2009) Interaction of HP1 and Brg1/Brm with the globular domain of histone H3 is required for HP1-mediated repression. PLoS Genet 5: e1000769. doi: 10.1371/journal.pgen.1000769 20011120

40. Friedman J, Cho WK, Chu CK, Keedy KS, Archin NM, et al. (2011) Epigenetic silencing of HIV-1 by the histone H3 lysine 27 methyltransferase enhancer of Zeste 2. J Virol 85: 9078–9089. doi: 10.1128/JVI.00836-11 21715480

41. Verma SK, Tian X, LaFrance LV, Duquenne C, Suarez DP, et al. (2012) Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2. ACS Med Chem Lett 3: 1091–1096. doi: 10.1021/ml3003346 24900432

42. Amatangelo MD, Garipov A, Li H, Conejo-Garcia JR, Speicher DW, et al. (2013) Three-dimensional culture sensitizes epithelial ovarian cancer cells to EZH2 methyltransferase inhibition. Cell Cycle 12: 2113–2119. doi: 10.4161/cc.25163 23759589

43. Margolis DM, Hazuda DJ (2013) Combined approaches for HIV cure. Curr Opin HIV AIDS 8: 230–235. doi: 10.1097/COH.0b013e32835ef089 23446138

44. Lopez-Cabrera M, Munoz E, Blazquez MV, Ursa MA, Santis AG, et al. (1995) Transcriptional regulation of the gene encoding the human C-type lectin leukocyte receptor AIM/CD69 and functional characterization of its tumor necrosis factor-alpha-responsive elements. J Biol Chem 270: 21545–21551. 7665567

45. Stacey AR, Norris PJ, Qin L, Haygreen EA, Taylor E, et al. (2009) Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J Virol 83: 3719–3733. doi: 10.1128/JVI.01844-08 19176632

46. Macal M, Sankaran S, Chun TW, Reay E, Flamm J, et al. (2008) Effective CD4+ T-cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with enhanced Th17 cells and polyfunctional HIV-specific T-cell responses. Mucosal Immunol 1: 475–488. doi: 10.1038/mi.2008.35 19079215

47. Guadalupe M, Sankaran S, George MD, Reay E, Verhoeven D, et al. (2006) Viral suppression and immune restoration in the gastrointestinal mucosa of human immunodeficiency virus type 1-infected patients initiating therapy during primary or chronic infection. J Virol 80: 8236–8247. 16873279

48. Don AS, Martinez-Lamenca C, Webb WR, Proia RL, Roberts E, et al. (2007) Essential requirement for sphingosine kinase 2 in a sphingolipid apoptosis pathway activated by FTY720 analogues. J Biol Chem 282: 15833–15842. 17400555

49. Ferreira PM, Lima DJ, Debiasi BW, Soares BM, Machado Kda C, et al. (2013) Antiproliferative activity of Rhinella marina and Rhaebo guttatus venom extracts from Southern Amazon. Toxicon 72: 43–51. doi: 10.1016/j.toxicon.2013.06.009 23796725

50. Johnson TM, Meade K, Pathak N, Marques MR, Attardi LD (2008) Knockin mice expressing a chimeric p53 protein reveal mechanistic differences in how p53 triggers apoptosis and senescence. Proc Natl Acad Sci U S A 105: 1215–1220. doi: 10.1073/pnas.0706764105 18216268

51. Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, et al. (2013) Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155: 540–551. doi: 10.1016/j.cell.2013.09.020 24243014

52. Kulkosky J, Culnan DM, Roman J, Dornadula G, Schnell M, et al. (2001) Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood 98: 3006–3015. 11698284

53. Mehla R, Bivalkar-Mehla S, Zhang R, Handy I, Albrecht H, et al. (2010) Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner. PLoS One 5: e11160. doi: 10.1371/journal.pone.0011160 20585398

54. Lucera M, Tilton CA, Mao H, Dobrowolski C, Tabler C, et al. (2014) The histone deacetylase inhibitor vorinostat (SAHA) increases the susceptibility of uninfected CD4+ T cells to HIV by increasing the kinetics and efficiency of post-entry viral events. J Virol.

55. Kalinina OV, Pfeifer N, Lengauer T (2013) Modelling binding between CCR5 and CXCR4 receptors and their ligands suggests the surface electrostatic potential of the co-receptor to be a key player in the HIV-1 tropism. Retrovirology 10: 130. doi: 10.1186/1742-4690-10-130 24215935

56. Bedoya LM, Marquez N, Martinez N, Gutierrez-Eisman S, Alvarez A, et al. (2009) SJ23B, a jatrophane diterpene activates classical PKCs and displays strong activity against HIV in vitro. Biochem Pharmacol 77: 965–978. doi: 10.1016/j.bcp.2008.11.025 19100719

57. Soriano-Sarabia N, Bateson RE, Dahl NP, Crooks AM, Kuruc JD, et al. (2014) The quantitation of replication-competent HIV-1 in populations of resting CD4+ T cells. J Virol.

58. Baldwin AS Jr. (2001) Series introduction: the transcription factor NF-kappaB and human disease. J Clin Invest 107: 3–6. 11134170

59. Zhou Q, Li T, Price DH (2012) RNA polymerase II elongation control. Annu Rev Biochem 81: 119–143. doi: 10.1146/annurev-biochem-052610-095910 22404626

60. Liang X, Grue-Sorensen G, Mansson K, Vedso P, Soor A, et al. (2013) Syntheses, biological evaluation and SAR of ingenol mebutate analogues for treatment of actinic keratosis and non-melanoma skin cancer. Bioorg Med Chem Lett 23: 5624–5629. doi: 10.1016/j.bmcl.2013.08.038 23993332

61. Sorg B, Schmidt R, Hecker E (1987) Structure/activity relationships of polyfunctional diterpenes of the ingenane type. I. Tumor-promoting activity of homologous, aliphatic 3-esters of ingenol and of delta 7,8-isoingenol-3-tetradecanoate. Carcinogenesis 8: 1–4. 3100081

62. Blanco-Molina M, Tron GC, Macho A, Lucena C, Calzado MA, et al. (2001) Ingenol esters induce apoptosis in Jurkat cells through an AP-1 and NF-kappaB independent pathway. Chem Biol 8: 767–778. 11514226

63. Blazkova J, Chun TW, Belay BW, Murray D, Justement JS, et al. (2012) Effect of histone deacetylase inhibitors on HIV production in latently infected, resting CD4(+) T cells from infected individuals receiving effective antiretroviral therapy. J Infect Dis 206: 765–769. doi: 10.1093/infdis/jis412 22732922

64. Chou TC (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58: 621–681. 16968952

65. Tripathy MK, McManamy ME, Burch BD, Archin NM, Margolis DM (2015) H3K27 demethylation at the proviral promoter sensitizes latent HIV to the effects of vorinostat in ex-vivo cultures of resting CD4+ T cells. J Virol.