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The Loss of Binary: Pushing the Herpesvirus Latency Paradigm

  • Virology (A Nicola, Section Editor)
  • Published:
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Abstract

Purpose of Review

Herpesvirus latency has been viewed as a binary state where replication is either on or off. During latency, gene expression is thought to be restricted to non-coding RNAs or very few proteins so that the virus avoids detection by the immune system. However, a number of recent studies across herpesvirus families call into question the existence of a binary switch for latency and suggest that latency is far more dynamic than originally presumed. These studies are the focus of this review.

Recent Findings

Highly sensitive and global approaches to investigate viral gene expression in the context of latency have revealed low-level viral transcripts and in some cases protein, from each of the three kinetic gene classes during the latent alpha and beta herpesvirus infection either in vitro or in vivo. Further, low-level, asymptomatic virus shedding persists following acute infection. Together, these findings have raised questions about how silent the latent infection truly is.

Summary

Emerging evidence suggests that viral gene expression associated with latent states may be broader and more dynamic than originally presumed during herpesvirus latency. This is an important possibility to consider in understanding the molecular programs associated with the establishment, maintenance, and reactivation of herpesvirus latency. Here, we review these findings and detail how they contribute to the emergence of a biphasic model of reactivation.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Roizman B, Knipe DM, Whitely RJ. Herpes simplex viruses. In: Knipe DM, Howley PM, editors. Fields virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. p. 1823–97.

    Google Scholar 

  2. Arvin AM, Gilden D. Varicella-zoster virus. In: Knipe DM, Howley PM, editors. Fields virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. p. 2015–57.

    Google Scholar 

  3. Mocarski E Jr, Shenk T, Griffiths PD, et al. Cytomegaloviruses. In: Knipe DM, Howley PM, editors. Fields virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. p. 1960–2014.

    Google Scholar 

  4. Longnecker RM, Kieff E, Cohen JI. Epstein-Barr Virus. In: Knipe DM, Howley PM, editors. Fields virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. p. 1898–959.

    Google Scholar 

  5. Damania BA, Cesarman E. Kaposi’s sarcoma-associated herpesvirus. In: Knipe DM, Howley PM, editors. Fields virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. p. 2080–128.

    Google Scholar 

  6. Wilcox CL, Johnson EM Jr. Nerve growth factor deprivation results in the reactivation of latent herpes simplex virus in vitro. J Virol. 1987;61(7):2311–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Wilcox CL, Johnson EM Jr. Characterization of nerve growth factor-dependent herpes simplex virus latency in neurons in vitro. J Virol. 1988;62(2):393–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kobayashi M, Kim JY, Camarena V et al. A primary neuron culture system for the study of herpes simplex virus latency and reactivation. J Vis Exp: JoVE. 2012;62. doi:10.3791/3823.

  9. Wilson AC, Mohr I. A cultured affair: HSV latency and reactivation in neurons. Trends Microbiol. 2012;20(12):604–11. doi:10.1016/j.tim.2012.08.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bertke AS, Swanson SM, Chen J, et al. A5-positive primary sensory neurons are nonpermissive for productive infection with herpes simplex virus 1 in vitro. J Virol. 2011;85(13):6669–77. doi:10.1128/jvi.00204-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Goodrum FD, Jordan CT, High K, et al. Human cytomegalovirus gene expression during infection of primary hematopoietic progenitor cells: a model for latency. Proc Natl Acad Sci U S A. 2002;99(25):16255–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Albright ER, Kalejta RF. Myeloblastic cell lines mimic some but not all aspects of human cytomegalovirus experimental latency defined in primary CD34+ cell populations. J Virol. 2013;87(17):9802–12. doi:10.1128/jvi.01436-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Arcangeletti MC, Vasile Simone R, Rodighiero I, et al. Human cytomegalovirus reactivation from latency: validation of a “switch” model in vitro. Virol J. 2016;13(1):179. doi:10.1186/s12985-016-0634-z.

    Article  PubMed  PubMed Central  Google Scholar 

  14. O'Connor CM, Murphy EA. A myeloid progenitor cell line capable of supporting human cytomegalovirus latency and reactivation, resulting in infectious progeny. J Virol. 2012;86(18):9854–65. doi:10.1128/jvi.01278-12.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Smith MS, Goldman DC, Bailey AS, et al. Granulocyte-colony stimulating factor reactivates human cytomegalovirus in a latently infected humanized mouse model. Cell Host Microbe. 2010;8(3):284–91. doi:10.1016/j.chom.2010.08.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kurz SK, Rapp M, Steffens HP, et al. Focal transcriptional activity of murine cytomegalovirus during latency in the lungs. J Virol. 1999;73(1):482–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Reddehase MJ, Simon CO, Seckert CK, et al. Murine model of cytomegalovirus latency and reactivation. Curr Top Microbiol Immunol. 2008;325:315–31.

    CAS  PubMed  Google Scholar 

  18. Stevens JG. Human herpesviruses: a consideration of the latent state. Microbiol Rev. 1989;53(3):318–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Pellett PE, Roizman B. Herpesviridae. In: Knipe DM, Howley PM, editors. Fields virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. p. 1802–22.

    Google Scholar 

  20. Spivack JG, Fraser NW. Detection of herpes simplex virus type 1 transcripts during latent infection in mice. J Virol. 1987;61(12):3841–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Stevens JG, Wagner EK, Devi-Rao GB, et al. RNA complementary to a herpesvirus alpha gene mRNA is prominent in latently infected neurons. Science (New York, NY). 1987;235(4792):1056–9.

    Article  CAS  Google Scholar 

  22. Caviness K, Bughio F, Crawford LB, et al. Complex interplay of the UL136 isoforms balances cytomegalovirus replication and latency. MBio. 2016;7(2):e01986. doi:10.1128/mBio.01986-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Umashankar M, Rak M, Bughio F, et al. Antagonistic determinants controlling replicative and latent states of human cytomegalovirus infection. J Virol. 2014;88(11):5987–6002.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Umashankar M, Petrucelli A, Cicchini L, et al. A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection. PLoS Pathog. 2011;7(12):e1002444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bego M, Maciejewski J, Khaiboullina S, et al. Characterization of an antisense transcript spanning the UL81-82 locus of human cytomegalovirus. J Virol. 2005;79(17):11022–34. doi:10.1128/jvi.79.17.11022-11034.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bego MG, Keyes LR, Maciejewski J, et al. Human cytomegalovirus latency-associated protein LUNA is expressed during HCMV infections in vivo. Arch Virol. 2011;156(10):1847–51. doi:10.1007/s00705-011-1027-7.

    Article  CAS  PubMed  Google Scholar 

  27. Piedade D, Azevedo-Pereira JM. The role of microRNAs in the pathogenesis of herpesvirus infection. Viruses. 2016;8(6). doi:10.3390/v8060156.

  28. Bloom DC. Alphaherpesvirus latency: a dynamic state of transcription and reactivation. Adv Virus Res. 2016;94:53–80. doi:10.1016/bs.aivir.2015.10.001.

    Article  PubMed  Google Scholar 

  29. Cheung AK, Abendroth A, Cunningham AL, et al. Viral gene expression during the establishment of human cytomegalovirus latent infection in myeloid progenitor cells. Blood. 2006;108(12):3691–9. doi:10.1182/blood-2005-12-026682.

    Article  CAS  PubMed  Google Scholar 

  30. Goodrum F, Reeves M, Sinclair J, et al. Human cytomegalovirus sequences expressed in latently infected individuals promote a latent infection in vitro. Blood. 2007;110(3):937–45. doi:10.1182/blood-2007-01-070078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cohrs RJ, Gilden DH. Varicella zoster virus transcription in latently-infected human ganglia. Anticancer Res. 2003;23(3a):2063–9.

    CAS  PubMed  Google Scholar 

  32. Kosz-Vnenchak M, Coen DM, Knipe DM. Restricted expression of herpes simplex virus lytic genes during establishment of latent infection by thymidine kinase-negative mutant viruses. J Virol. 1990;64(11):5396–402.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Rossetto CC, Tarrant-Elorza M, Pari GS. Cis and trans acting factors involved in human cytomegalovirus experimental and natural latent infection of CD14 (+) monocytes and CD34 (+) cells. PLoS Pathog. 2013;9(5):e1003366. doi:10.1371/journal.ppat.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kramer MF, Chen SH, Knipe DM, et al. Accumulation of viral transcripts and DNA during establishment of latency by herpes simplex virus. J Virol. 1998;72(2):1177–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kramer MF, Coen DM. Quantification of transcripts from the ICP4 and thymidine kinase genes in mouse ganglia latently infected with herpes simplex virus. J Virol. 1995;69(3):1389–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Giordani NV, Neumann DM, Kwiatkowski DL, et al. During herpes simplex virus type 1 infection of rabbits, the ability to express the latency-associated transcript increases latent-phase transcription of lytic genes. J Virol. 2008;82(12):6056–60. doi:10.1128/jvi.02661-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Proenca JT, Coleman HM, Connor V, et al. A historical analysis of herpes simplex virus promoter activation in vivo reveals distinct populations of latently infected neurones. J Gen Virol. 2008;89(Pt 12):2965–74. doi:10.1099/vir.0.2008/005066-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. • Ma JZ, Russell TA, Spelman T, et al. Lytic gene expression is frequent in HSV-1 latent infection and correlates with the engagement of a cell-intrinsic transcriptional response. PLoS Pathog. 2014;10(7):e1004237. doi:10.1371/journal.ppat.1004237. This study uses single-cell transcription analysis to reveal the highly dynamic nature of HSV latency. It is the first to show that lytic HSV-1 gene expression occurs frequently in the majority of latently infected neurons.

    Article  PubMed  PubMed Central  Google Scholar 

  39. • Russell TA, Tscharke DC. Lytic promoters express protein during herpes simplex virus latency. PLoS Pathog. 2016;12(6):e1005729. doi:10.1371/journal.ppat.1005729. A follow-up study to Ma et al (2014); this study shows that lytic protein is expressed during latent HSV-1 infection.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Chen SH, Lee LY, Garber DA, et al. Neither LAT nor open reading frame P mutations increase expression of spliced or intron-containing ICP0 transcripts in mouse ganglia latently infected with herpes simplex virus. J Virol. 2002;76(10):4764–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Maillet S, Naas T, Crepin S, et al. Herpes simplex virus type 1 latently infected neurons differentially express latency-associated and ICP0 transcripts. J Virol. 2006;80(18):9310–21. doi:10.1128/jvi.02615-05.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Proenca JT, Coleman HM, Nicoll MP, et al. An investigation of herpes simplex virus promoter activity compatible with latency establishment reveals VP16-independent activation of immediate-early promoters in sensory neurones. J Gen Virol. 2011;92(Pt 11):2575–85. doi:10.1099/vir.0.034728-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Leib DA, Coen DM, Bogard CL, et al. Immediate-early regulatory gene mutants define different stages in the establishment and reactivation of herpes simplex virus latency. J Virol. 1989;63(2):759–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Halford WP, Schaffer PA. ICP0 is required for efficient reactivation of herpes simplex virus type 1 from neuronal latency. J Virol. 2001;75(7):3240–9. doi:10.1128/jvi.75.7.3240-3249.2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. • Raja P, Lee JS, Pan D et al. A herpesviral lytic protein regulates the structure of latent viral chromatin. mBio. 2016;7(3). doi:10.1128/mBio.00633-16. This study shows that the HSV lytic protein ICP0 is functional during latent infection and influences the latent environment by driving LAT expression and regulating viral chromatin.

  46. Goodrum F, Jordan CT, Terhune SS, et al. Differential outcomes of human cytomegalovirus infection in primitive hematopoietic cell subpopulations. Blood. 2004;104(3):687–95. doi:10.1182/blood-2003-12-4344.

    Article  CAS  PubMed  Google Scholar 

  47. Taylor-Wiedeman J, Sissons P, Sinclair J. Induction of endogenous human cytomegalovirus gene expression after differentiation of monocytes from healthy carriers. J Virol. 1994;68:1597–604.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Grzimek NK, Dreis D, Schmalz S, et al. Random, asynchronous, and asymmetric transcriptional activity of enhancer-flanking major immediate-early genes ie1/3 and ie2 during murine cytomegalovirus latency in the lungs. J Virol. 2001;75(6):2692–705. doi:10.1128/jvi.75.6.2692-2705.2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kurz SK, Reddehase MJ. Patchwork pattern of transcriptional reactivation in the lungs indicates sequential checkpoints in the transition from murine cytomegalovirus latency to recurrence. J Virol. 1999;73(10):8612–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Corey L, Wald A, Davis LG. Subclinical shedding of HSV: its potential for reduction by antiviral therapy. Adv Exp Med Biol. 1996;394:11–6.

    Article  CAS  PubMed  Google Scholar 

  51. Wald A, Zeh J, Selke S, et al. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med. 2000;342(12):844–50. doi:10.1056/nejm200003233421203.

    Article  CAS  PubMed  Google Scholar 

  52. Tronstein E, Johnston C, Huang ML, et al. Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA. 2011;305(14):1441–9. doi:10.1001/jama.2011.420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Miller CS, Danaher RJ. Asymptomatic shedding of herpes simplex virus (HSV) in the oral cavity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105(1):43–50. doi:10.1016/j.tripleo.2007.06.011.

    Article  PubMed  Google Scholar 

  54. Berman EJ, Hill JM. Spontaneous ocular shedding of HSV-1 in latently infected rabbits. Invest Ophthalmol Vis Sci. 1985;26(4):587–90.

    CAS  PubMed  Google Scholar 

  55. Margolis TP, Elfman FL, Leib D, et al. Spontaneous reactivation of herpes simplex virus type 1 in latently infected murine sensory ganglia. J Virol. 2007;81(20):11069–74. doi:10.1128/jvi.00243-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Pass RF, Hutto SC, Reynolds DW, et al. Increased frequency of cytomegalovirus infection in children in group day care. Pediatrics. 1984;74(1):121–6.

    CAS  PubMed  Google Scholar 

  57. Britt W. Manifestations of human cytomegalovirus infection: proposed mechanisms of acute and chronic disease. Curr Top Microbiol Immunol. 2008;325:417–70.

    CAS  PubMed  Google Scholar 

  58. Sylwester AW, Mitchell BL, Edgar JB, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med. 2005;202(5):673–85. doi:10.1084/jem.20050882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chidrawar S, Khan N, Wei W, et al. Cytomegalovirus-seropositivity has a profound influence on the magnitude of major lymphoid subsets within healthy individuals. Clin Exp Immunol. 2009;155(3):423–32. doi:10.1111/j.1365-2249.2008.03785.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Krishna BA, Lau B, Jackson SE, et al. Transient activation of human cytomegalovirus lytic gene expression during latency allows cytotoxic T cell killing of latently infected cells. Sci Rep. 2016;6:24674. doi:10.1038/srep24674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chen HS, Lu F, Lieberman PM. Epigenetic regulation of EBV and KSHV latency. Curr Opin Virol. 2013;3(3):251–9. doi:10.1016/j.coviro.2013.03.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lieberman PM. Keeping it quiet: chromatin control of gammaherpesvirus latency. Nat Rev Microbiol. 2013;11(12):863–75. doi:10.1038/nrmicro3135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sinclair J. Chromatin structure regulates human cytomegalovirus gene expression during latency, reactivation and lytic infection. Biochim Biophys Acta. 2010;1799(3–4):286–95. doi:10.1016/j.bbagrm.2009.08.001.

    Article  CAS  PubMed  Google Scholar 

  64. Cliffe AR, Garber DA, Knipe DM. Transcription of the herpes simplex virus latency-associated transcript promotes the formation of facultative heterochromatin on lytic promoters. J Virol. 2009;83(16):8182–90. doi:10.1128/jvi.00712-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kwiatkowski DL, Thompson HW, Bloom DC. The polycomb group protein Bmi1 binds to the herpes simplex virus 1 latent genome and maintains repressive histone marks during latency. J Virol. 2009;83(16):8173–81. doi:10.1128/jvi.00686-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hill JM, Quenelle DC, Cardin RD, et al. Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes. Sci Transl Med. 2014;6(265):265ra169. doi:10.1126/scitranslmed.3010643.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Kubat NJ, Amelio AL, Giordani NV, et al. The herpes simplex virus type 1 latency-associated transcript (LAT) enhancer/rcr is hyperacetylated during latency independently of LAT transcription. J Virol. 2004;78(22):12508–18. doi:10.1128/jvi.78.22.12508-12518.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kubat NJ, Tran RK, McAnany P, et al. Specific histone tail modification and not DNA methylation is a determinant of herpes simplex virus type 1 latent gene expression. J Virol. 2004;78(3):1139–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Neumann DM, Bhattacharjee PS, Giordani NV, et al. In vivo changes in the patterns of chromatin structure associated with the latent herpes simplex virus type 1 genome in mouse trigeminal ganglia can be detected at early times after butyrate treatment. J Virol. 2007;81(23):13248–53. doi:10.1128/jvi.01569-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Leib DA, Bogard CL, Kosz-Vnenchak M, et al. A deletion mutant of the latency-associated transcript of herpes simplex virus type 1 reactivates from the latent state with reduced frequency. J Virol. 1989;63(7):2893–900.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Garber DA, Schaffer PA, Knipe DM. A LAT-associated function reduces productive-cycle gene expression during acute infection of murine sensory neurons with herpes simplex virus type 1. J Virol. 1997;71(8):5885–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Devi-Rao GB, Bloom DC, Stevens JG, et al. Herpes simplex virus type 1 DNA replication and gene expression during explant-induced reactivation of latently infected murine sensory ganglia. J Virol. 1994;68(3):1271–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Chen SH, Kramer MF, Schaffer PA, et al. A viral function represses accumulation of transcripts from productive-cycle genes in mouse ganglia latently infected with herpes simplex virus. J Virol. 1997;71(8):5878–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Nicoll MP, Hann W, Shivkumar M, et al. The HSV-1 latency-associated transcript functions to repress latent phase lytic gene expression and suppress virus reactivation from latently infected neurons. PLoS Pathog. 2016;12(4):e1005539. doi:10.1371/journal.ppat.1005539.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Wang QY, Zhou C, Johnson KE, et al. Herpesviral latency-associated transcript gene promotes assembly of heterochromatin on viral lytic-gene promoters in latent infection. Proc Natl Acad Sci U S A. 2005;102(44):16055–9. doi:10.1073/pnas.0505850102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hummel M, Yan S, Li Z, et al. Transcriptional reactivation of murine cytomegalovirus ie gene expression by 5-aza-2′-deoxycytidine and trichostatin A in latently infected cells despite lack of methylation of the major immediate-early promoter. J Gen Virol. 2007;88(Pt 4):1097–102. doi:10.1099/vir.0.82696-0.

    Article  CAS  PubMed  Google Scholar 

  77. Murphy JC, Fischle W, Verdin E, et al. Control of cytomegalovirus lytic gene expression by histone acetylation. EMBO J. 2002;21(5):1112–20. doi:10.1093/emboj/21.5.1112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Nitzsche A, Paulus C, Nevels M. Temporal dynamics of cytomegalovirus chromatin assembly in productively infected human cells. J Virol. 2008;82(22):11167–80. doi:10.1128/jvi.01218-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Liu XF, Yan S, Abecassis M, et al. Biphasic recruitment of transcriptional repressors to the murine cytomegalovirus major immediate-early promoter during the course of infection in vivo. J Virol. 2010;84(7):3631–43. doi:10.1128/jvi.02380-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Reeves MB, MacAry PA, Lehner PJ, et al. Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc Natl Acad Sci U S A. 2005;102(11):4140–5. doi:10.1073/pnas.0408994102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Reeves MB, Sinclair JH. Analysis of latent viral gene expression in natural and experimental latency models of human cytomegalovirus and its correlation with histone modifications at a latent promoter. J Gen Virol. 2010;91(Pt 3):599–604. doi:10.1099/vir.0.015602-0.

    Article  CAS  PubMed  Google Scholar 

  82. Abraham CG, Kulesza CA. Polycomb repressive complex 2 silences human cytomegalovirus transcription in quiescent infection models. J Virol. 2013;87(24):13193–205. doi:10.1128/jvi.02420-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Henry SC, Hamilton JD. Detection of murine cytomegalovirus immediate early 1 transcripts in the spleens of latently infected mice. J Infect Dis. 1993;167(4):950–4.

    Article  CAS  PubMed  Google Scholar 

  84. Yu Y, Henry SC, Xu F, et al. Expression of a murine cytomegalovirus early-late protein in “latently” infected mice. J Infect Dis. 1995;172(2):371–9.

    Article  CAS  PubMed  Google Scholar 

  85. Yuhasz SA, Dissette VB, Cook ML, et al. Murine cytomegalovirus is present in both chronic active and latent states in persistently infected mice. Virology. 1994;202(1):272–80. doi:10.1006/viro.1994.1343.

    Article  CAS  PubMed  Google Scholar 

  86. Kim JY, Mandarino A, Chao MV, et al. Transient reversal of episome silencing precedes VP16-dependent transcription during reactivation of latent HSV-1 in neurons. PLoS Pathog. 2012;8(2):e1002540. doi:10.1371/journal.ppat.1002540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Penkert RR, Kalejta RF. Tegument protein control of latent herpesvirus establishment and animation. Herpesviridae. 2011;2(1):3. doi:10.1186/2042-4280-2-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Thompson RL, Preston CM, Sawtell NM. De novo synthesis of VP16 coordinates the exit from HSV latency in vivo. PLoS Pathog. 2009;5(3):e1000352. doi:10.1371/journal.ppat.1000352.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Du T, Zhou G, Roizman B. HSV-1 gene expression from reactivated ganglia is disordered and concurrent with suppression of latency-associated transcript and miRNAs. Proc Natl Acad Sci U S A. 2011;108(46):18820–4. doi:10.1073/pnas.1117203108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. • Cliffe AR, Arbuckle JH, Vogel JL, et al. Neuronal stress pathway mediating a histone methyl/phospho switch is required for herpes simplex virus reactivation. Cell Host Microbe. 2015;18(6):649–58. doi:10.1016/j.chom.2015.11.007. This study is the first report of a cellular reactivation stimulus activating silenced promoters to induce HSV lytic gene expression. It describes a mechanism by which JNK signaling activates a histone methyl/phospho switch to bypass repressive lysine methylation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Soderberg-Naucler C, Streblow DN, Fish KN, et al. Reactivation of latent human cytomegalovirus in CD14(+) monocytes is differentiation dependent. J Virol. 2001;75:7543–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Soderberg-Naucler C, Fish KN, Nelson JA. Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell. 1997;91(1):119–26.

    Article  CAS  PubMed  Google Scholar 

  93. Reeves MB, Sinclair JH. Circulating dendritic cells isolated from healthy seropositive donors are sites of human cytomegalovirus reactivation in vivo. J Virol. 2013;87(19):10660–7. doi:10.1128/jvi.01539-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Buehler J, Zeltzer S, Reitsma J, et al. Opposing regulation of the EGF receptor: a molecular switch controlling cytomegalovirus latency and replication. PLoS Pathog. 2016;12(5):e1005655. doi:10.1371/journal.ppat.1005655.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Camarena V, Kobayashi M, Kim JY, et al. Nature and duration of growth factor signaling through receptor tyrosine kinases regulates HSV-1 latency in neurons. Cell Host Microbe. 2010;8(4):320–30. doi:10.1016/j.chom.2010.09.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Petrucelli A, Rak M, Grainger L, et al. Characterization of a novel Golgi apparatus-localized latency determinant encoded by human cytomegalovirus. J Virol. 2009;83(11):5615–29. doi:10.1128/jvi.01989-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lee SH, Caviness K, Albright ER, et al. Long and short isoforms of the human cytomegalovirus UL138 protein silence IE transcription and promote latency. J Virol. 2016;90(20):9483–94. doi:10.1128/jvi.01547-16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. BIO5 Institute, University of Arizona, 1657 E. Helen St, Thomas W. Keating Bldg., Tucson, AZ, 85721, USA

    Donna Collins-McMillen & Felicia D. Goodrum

  2. Department of Immunobiology, Department of Cellular and Molecular Medicine, Department of Molecular and Cellular Biology, Arizona Center on Aging, University of Arizona Cancer Center, University of Arizona, 1657 E. Helen St, Thomas W. Keating Bldg., Tucson, AZ, 85721, USA

    Felicia D. Goodrum

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  1. Donna Collins-McMillen
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  2. Felicia D. Goodrum
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Correspondence to Felicia D. Goodrum.

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This article is part of the Topical Collection on Virology

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Collins-McMillen, D., Goodrum, F.D. The Loss of Binary: Pushing the Herpesvirus Latency Paradigm. Curr Clin Micro Rpt 4, 124–131 (2017). https://doi.org/10.1007/s40588-017-0072-8

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  • DOI: https://doi.org/10.1007/s40588-017-0072-8

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