Modeling the Effects of Vorinostat Reveals both Transient and Delayed HIV Transcriptional Activation and Minimal Killing of Latently Infected Cells

1. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, et al. (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. New England Journal of Medicine 338 : 853–860. 9516219

2. Phillips AN, Neaton J, Lundgren JD (2008) The role of HIV in serious diseases other than AIDS. AIDS 22 : 2409–2418. doi: 10.1097/QAD.0b013e3283174636 19005264

3. Deeks SG, Autran B, Berkhout B, Benkirane M, Cairns S, et al. (2012) Towards an HIV cure: a global scientific strategy. Nat Rev Immunol 12 : 607–614. doi: 10.1038/nri3262 22814509

4. 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

5. 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

6. Deeks SG (2012) HIV: Shock and kill. Nature 487 : 439–440. doi: 10.1038/487439a 22836995

7. Van Lint C, Emiliani S, Ott M, Verdin E (1996) Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. Embo Journal 15 : 1112–1120. 8605881

8. Peart MJ, Smyth GK, van Laar RK, Bowtell DD, Richon VM, et al. (2005) Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci U S A 102 : 3697–3702. 15738394

9. Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R (2007) FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12 : 1247–1252. 17962618

10. 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

11. 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

12. Nowak M, May R (2001) Virus dynamics: Mathematical principles of immunology and virology.: Oxford University Press. 256 p.

13. Perelson AS, Nelson PW (1999) Mathematical analysis of HIV-1 dynamics in vivo. Siam Review 41 : 3–44.

14. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD (1996) HIV-1 dynamics in vivo: Virion clearance rate, infected cell life-span, and viral generation time. Science 271 : 1582–1586. 8599114

15. Rong LB, Perelson AS (2009) Asymmetric division of activated latently infected cells may explain the decay kinetics of the HIV-1 latent reservoir and intermittent viral blips. Mathematical Biosciences 217 : 77–87. doi: 10.1016/j.mbs.2008.10.006 18977369

16. Rong L, Perelson AS (2009) Modeling HIV persistence, the latent reservoir, and viral blips. J Theor Biol 260 : 308–331. doi: 10.1016/j.jtbi.2009.06.011 19539630

17. Rong L, Perelson AS (2009) Modeling latently infected cell activation: viral and latent reservoir persistence, and viral blips in HIV-infected patients on potent therapy. PLoS Comput Biol 5: e1000533. doi: 10.1371/journal.pcbi.1000533 19834532

18. Hill AL, Rosenbloom DI, Fu F, Nowak MA, Siliciano RF (2014) Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1. Proc Natl Acad Sci U S A 111 : 13475–13480. doi: 10.1073/pnas.1406663111 25097264

19. Petravic J, Martyushev A, Reece JC, Kent SJ, Davenport MP (2014) Modeling the timing of antilatency drug administration during HIV treatment. J Virol 88 : 14050–14056. doi: 10.1128/JVI.01701-14 25253352

20. Mohammadi P, di Iulio J, Munoz M, Martinez R, Bartha I, et al. (2014) Dynamics of HIV latency and reactivation in a primary CD4+ T cell model. PLoS Pathog 10: e1004156. doi: 10.1371/journal.ppat.1004156 24875931

21. Cillo AR, Sobolewski MD, Bosch RJ, Fyne E, Piatak M Jr., et al. (2014) Quantification of HIV-1 latency reversal in resting CD4+ T cells from patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A 111 : 7078–7083. doi: 10.1073/pnas.1402873111 24706775

22. 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

23. Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, et al. (1997) Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387 : 183–188. 9144289

24. Mohri H, Bonhoeffer S, Monard S, Perelson AS, Ho DD (1998) Rapid turnover of T lymphocytes in SIV-infected rhesus macaques. Science 279 : 1223–1227. 9469816

25. Perelson AS, Kirschner DE, De Boer R (1993) Dynamics of HIV infection of CD4+ T cells. Math Biosci 114 : 81–125. 8096155

26. Jones LE, Perelson AS (2007) Transient viremia, plasma viral load, and reservoir replenishment in HIV-infected patients on antiretroviral therapy. J Acquir Immune Defic Syndr 45 : 483–493. 17496565

27. Markowitz M, Louie M, Hurley A, Sun E, Di Mascio M, et al. (2003) A novel antiviral intervention results in more accurate assessment of human immunodeficiency virus type 1 replication dynamics and T-cell decay in vivo. J Virol 77 : 5037–5038. 12663814

28. Kim H, Yin J (2005) Robust growth of human immunodeficiency virus type 1 (HIV-1). Biophys J 89 : 2210–2221. 16055539

29. Malim MH, Cullen BR (1993) Rev and the fate of pre-mRNA in the nucleus: implications for the regulation of RNA processing in eukaryotes. Mol Cell Biol 13 : 6180–6189. 8105371

30. Blanchard JM, Weber J, Jelinek W, Darnell JE (1978) In vitro RNA-RNA splicing in adenovirus 2 mRNA formation. Proc Natl Acad Sci U S A 75 : 5344–5348. 281684

31. Hockett RD, Kilby JM, Derdeyn CA, Saag MS, Sillers M, et al. (1999) Constant mean viral copy number per infected cell in tissues regardless of high, low, or undetectable plasma HIV RNA. J Exp Med 189 : 1545–1554. 10330433

32. Chen HY, Di Mascio M, Perelson AS, Ho DD, Zhang L (2007) Determination of virus burst size in vivo using a single-cycle SIV in rhesus macaques. Proc Natl Acad Sci U S A 104 : 19079–19084. 18025463

33. Ramratnam B, Bonhoeffer S, Binley J, Hurley A, Zhang L, et al. (1999) Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis. Lancet 354 : 1782–1785. 10577640

34. Razooky BS, Pai A, Aull K, Rouzine IM, Weinberger LS (2015) A hardwired HIV latency program. Cell 160 : 990–1001. doi: 10.1016/j.cell.2015.02.009 25723172

35. Weinberger LS, Dar RD, Simpson ML (2008) Transient-mediated fate determination in a transcriptional circuit of HIV. Nat Genet 40 : 466–470. doi: 10.1038/ng.116 18344999

36. Weinberger LS, Burnett JC, Toettcher JE, Arkin AP, Schaffer DV (2005) Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity. Cell 122 : 169–182. 16051143

37. Burnett JC, Miller-Jensen K, Shah PS, Arkin AP, Schaffer DV (2009) Control of stochastic gene expression by host factors at the HIV promoter. PLoS Pathog 5: e1000260. doi: 10.1371/journal.ppat.1000260 19132086

38. Pagans S, Pedal A, North BJ, Kaehlcke K, Marshall BL, et al. (2005) SIRT1 regulates HIV transcription via Tat deacetylation. PLoS Biol 3: e41. 15719057

39. Chen L, Fischle W, Verdin E, Greene WC (2001) Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 293 : 1653–1657. 11533489

40. Barboric M, Nissen RM, Kanazawa S, Jabrane-Ferrat N, Peterlin BM (2001) NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Molecular Cell 8 : 327–337. 11545735

41. Romerio F, Gabriel MN, Margolis DM (1997) Repression of human immunodeficiency virus type 1 through the novel cooperation of human factors YY1 and LSF. J Virol 71 : 9375–9382. 9371597

42. Budhiraja S, Famiglietti M, Bosque A, Planelles V, Rice AP (2013) Cyclin T1 and CDK9 T-loop phosphorylation are downregulated during establishment of HIV-1 latency in primary resting memory CD4+ T cells. J Virol 87 : 1211–1220. doi: 10.1128/JVI.02413-12 23152527

43. Bartholomeeusen K, Fujinaga K, Xiang YH, Peterlin BM (2013) Histone deacetylase inhibitors (HDACis) that release the positive transcription elongation factor b (P-TEFb) from its inhibitory complex also activate HIV transcription. Journal of Biological Chemistry 288 : 14400–14407. doi: 10.1074/jbc.M113.464834 23539624

44. Coiras M, Lopez-Huertas MR, Rullas J, Mittelbrunn M, Alcami J (2007) Basal shuttle of NF-kappaB/I kappaB alpha in resting T lymphocytes regulates HIV-1 LTR dependent expression. Retrovirology 4 : 56. 17686171

45. Ganesh L, Burstein E, Guha-Niyogi A, Louder MK, Mascola JR, et al. (2003) The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes. Nature 426 : 853–857. 14685242

46. Jakobsen MR, Mogensen TH, Paludan SR (2013) Caught in translation: innate restriction of HIV mRNA translation by a schlafen family protein. Cell Res 23 : 320–322. doi: 10.1038/cr.2012.155 23128674

47. Neil SJ, Zang T, Bieniasz PD (2008) Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451 : 425–430. doi: 10.1038/nature06553 18200009

48. Mittler JE, Sulzer B, Neumann AU, Perelson AS (1998) Influence of delayed viral production on viral dynamics in HIV-1 infected patients. Mathematical Biosciences 152 : 143–163. 9780612

49. MacDonald N (1989) Biological delay systems: linear stability theory. Cambridge: Cambridge University Press. 248 p.

50. Kim H, Perelson AS (2006) Viral and latent reservoir persistence in HIV-1-infected patients on therapy. PLoS Comput Biol 2: e135. 17040122

51. White CH, Johnston HE, Moesker B, Manousopoulou A, Margolis DM, et al. (2015) Mixed effects of suberoylanilide hydroxamic acid (SAHA) on the host transcriptome and proteome and their implications for HIV reactivation from latency. Antiviral Res 123 : 78–85. doi: 10.1016/j.antiviral.2015.09.002 26343910

52. Archin NM, Bateson R, Tripathy MK, Crooks AM, Yang KH, et al. (2014) HIV-1 expression within resting CD4(+) T cells after multiple doses of vorinostat. Journal of Infectious Diseases 210 : 728–735. doi: 10.1093/infdis/jiu155 24620025

53. 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

54. Pasternak A, O'Doherty U, Berkhout B (2015) Minor contribution of host-HIV readthrough transcripts to the level of HIV-1 gag RNA. The annual conference on retroviruses and opportunistic infections (CROI). Seattle, Washington.

55. 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

56. 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

57. Archin NM, Vaidya NK, Kuruc JD, Liberty AL, Wiegand A, et al. (2012) Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proc Natl Acad Sci U S A 109 : 9523–9528. doi: 10.1073/pnas.1120248109 22645358

58. Sogaard OS, Graversen ME, Leth S, Olesen R, Brinkmann CR, et al. (2015) The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo. PLoS Pathog 11: e1005142. doi: 10.1371/journal.ppat.1005142 26379282

59. Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, et al. (2014) Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. Lancet HIV 1: e13–21. doi: 10.1016/S2352-3018(14)70014-1 26423811

60. Holte SE, Melvin AJ, Mullins JI, Tobin NH, Frenkel LM (2006) Density-dependent decay in HIV-1 dynamics. J Acquir Immune Defic Syndr 41 : 266–276. 16540927

61. Callaway DS, Perelson AS (2002) HIV-1 infection and low steady state viral loads. Bull Math Biol 64 : 29–64. 11868336

62. Conway JM, Coombs D (2011) A stochastic model of latently infected cell reactivation and viral blip generation in treated HIV patients. PLoS Comput Biol 7: e1002033. doi: 10.1371/journal.pcbi.1002033 21552334

63. Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, 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. 10229227

64. Lewin B (2000) Genes VII. New York: Oxford University Press. 990 p.

65. Graeble MA, Churcher MJ, Lowe AD, Gait MJ, Karn J (1993) Human immunodeficiency virus type 1 transactivator protein, tat, stimulates transcriptional read-through of distal terminator sequences in vitro. Proc Natl Acad Sci U S A 90 : 6184–6188. 8327498

66. Nelder JA, Mead R (1965) A simplex-method for function minimization. Computer Journal 7 : 308–313.

67. Burnham KP, Anderson DR (2002) Model selection and multimodel inference: a practical information-theoretic approach. New York: Springer. 488 p.