Skip to main content
PMC home page
Virologica Sinica logoLink to Virologica Sinica
. 2014 Nov 25;29(6):343–352. doi: 10.1007/s12250-014-3532-9

Immediate-Early (IE) gene regulation of cytomegalovirus: IE1- and pp71-mediated viral strategies against cellular defenses

Lilith Torres 1, Qiyi Tang 1,✉
PMCID: PMC4654928  NIHMSID: NIHMS727752  PMID: 25501994

Abstract

Three crucial hurdles hinder studies on human cytomegalovirus (HCMV): strict species specificity, differences between in vivo and in vitro infection, and the complexity of gene regulation. Ever since the sequencing of the whole genome was first accomplished, functional studies on individual genes have been the mainstream in the CMV field. Gene regulation has therefore been elucidated in a more detailed fashion. However, viral gene regulation is largely controlled by both cellular and viral components. In other words, viral gene expression is determined by the virus-host interaction. Generally, cells respond to viral infection in a defensive pattern; at the same time, viruses try to counteract the cellular defense or else hide in the host (latency). Viruses evolve effective strategies against cellular defense in order to achieve replicative success. Whether or not they are successful, cellular defenses remain in the whole viral replication cycle: entry, immediate-early (IE) gene expression, early gene expression, DNA replication, late gene expression, and viral egress. Many viral strategies against cellular defense, and which occur in the immediate-early time of viral infection, have been documented. In this review, we will summarize the documented biological functions of IE1 and pp71 proteins, especially with regard to how they counteract cellular intrinsic defenses.

Keywords: cytomegalovirus (CMV), major immediate early promoter (MIEP), IE1, pp71, nuclear domain 10 (ND10), intrinsic cellular defense, enhancer, virus-host interaction

References

  1. Adler M, Tavalai N, Muller R, Stamminger T. Human cytomegalovirus immediate-early gene expression is restricted by the nuclear domain 10 component Sp100. J Gen Virol. 2011;92:1532–1538. doi: 10.1099/vir.0.030981-0. [DOI] [PubMed] [Google Scholar]
  2. Ahn J H, Hayward G S. The major immediate-early proteins IE1 and IE2 of human cytomegalovirus colocalize with and disrupt PML-associated nuclear bodies at very early times in infected permissive cells. J Virol. 1997;71:4599–4613. doi: 10.1128/jvi.71.6.4599-4613.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anderson K P, Fox M C, Brown-Driver V, Martin M J, Azad R F. Inhibition of human cytomegalovirus immediate-early gene expression by an antisense oligonucleotide complementary to immediate-early RNA. Antimicrob Agents Chemother. 1996;40:2004–2011. doi: 10.1128/aac.40.9.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Angulo A, Ghazal P. Regulation of human cytomegalovirus by retinoic acid. Scand J Infect Dis Suppl. 1995;99:113–115. [PubMed] [Google Scholar]
  5. Angulo A, Suto C, Heyman R A, Ghazal P. Characterization of the sequences of the human cytomegalovirus enhancer that mediate differential regulation by natural and synthetic retinoids. Mol Endocrinol. 1996;10:781–793. doi: 10.1210/mend.10.7.8813719. [DOI] [PubMed] [Google Scholar]
  6. Angulo A, Messerle M, Koszinowski U H, Ghazal P. Enhancer requirement for murine cytomegalovirus growth and genetic complementation by the human cytomegalovirus enhancer. J Virol. 1998;72:8502–8509. doi: 10.1128/jvi.72.11.8502-8509.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Angulo A, Kerry D, Huang H, Borst E M, Razinsky A, Wu J, Hobom U, Messerle M, Ghazal P. Identification of a boundary domain adjacent to the potent human cytomegalovirus enhancer that represses transcription of the divergent UL127 promoter. J Virol. 2000;74:2826–2839. doi: 10.1128/JVI.74.6.2826-2839.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Baldick C J, Jr., Marchini A, Patterson C E, Shenk T. Human cytomegalovirus tegument protein pp71 (ppUL82) enhances the infectivity of viral DNA and accelerates the infectious cycle. J Virol. 1997;71:4400–4408. doi: 10.1128/jvi.71.6.4400-4408.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bresnahan W A, Shenk T E. UL82 virion protein activates expression of immediate early viral genes in human cytomegalovirus-infected cells. Proc Natl Acad Sci U S A. 2000;97:14506–14511. doi: 10.1073/pnas.97.26.14506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Britt W J. Vaccines against human cytomegalovirus: time to test. Trends Microbiol. 1996;4:34–38. doi: 10.1016/0966-842X(96)81503-4. [DOI] [PubMed] [Google Scholar]
  11. Chau N H, Vanson C D, Kerry J A. Transcriptional regulation of the human cytomegalovirus US11 early gene. J Virol. 1999;73:863–870. doi: 10.1128/jvi.73.2.863-870.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chelbi-Alix M K, de The H. Herpes virus induced proteasome-dependent degradation of the nuclear bodies-associated PML and Sp100 proteins. Oncogene. 1999;18:935–941. doi: 10.1038/sj.onc.1202366. [DOI] [PubMed] [Google Scholar]
  13. Cherrington J M, Khoury E L, Mocarski E S. Human cytomegalovirus ie2 negatively regulates alpha gene expression via a short target sequence near the transcription start site. J Virol. 1991;65:887–896. doi: 10.1128/jvi.65.2.887-896.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chou S, Marousek G, Guentzel S, Follansbee S E, Poscher M E, Lalezari J P, Miner R C, Drew W L. Evolution of mutations conferring multidrug resistance during prophylaxis and therapy for cytomegalovirus disease. J Infect Dis. 1997;176:786–789. doi: 10.1086/517302. [DOI] [PubMed] [Google Scholar]
  15. Cosme R C, Martinez F P, Tang Q. Functional interaction of nuclear domain 10 and its components with cytomegalovirus after infections: cross-species host cells versus native cells. PLoS One. 2011;6:e19187. doi: 10.1371/journal.pone.0019187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Cosme R S, Yamamura Y, Tang Q. Roles of polypyrimidine tract binding proteins in major immediate-early gene expression and viral replication of human cytomegalovirus. J Virol. 2009;83:2839–2850. doi: 10.1128/JVI.02407-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Everett R D, Freemont P, Saitoh H, Dasso M, Orr A, Kathoria M, Parkinson J. The disruption of ND10 during herpes simplex virus infection correlates with the Vmw110- and proteasome-dependent loss of several PML isoforms. J Virol. 1998;72:6581–6591. doi: 10.1128/jvi.72.8.6581-6591.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Garcia-Ramirez J J, Ruchti F, Huang H, Simmen K, Angulo A, Ghazal P. Dominance of virus over host factors in cross-species activation of human cytomegalovirus early gene expression. J Virol. 2001;75:26–35. doi: 10.1128/JVI.75.1.26-35.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gawn J M, Greaves R F. Absence of IE1 p72 protein function during low-multiplicity infection by human cytomegalovirus results in a broad block to viral delayed-early gene expression. J Virol. 2002;76:4441–4455. doi: 10.1128/JVI.76.9.4441-4455.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Greaves R F, Mocarski E S. Defective growth correlates with reduced accumulation of a viral DNA replication protein after low-multiplicity infection by a human cytomegalovirus ie1 mutant. J Virol. 1998;72:366–379. doi: 10.1128/jvi.72.1.366-379.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gu H, Roizman B. The degradation of promyelocytic leukemia and Sp100 proteins by herpes simplex virus 1 is mediated by the ubiquitin-conjugating enzyme UbcH5a. Proc Natl Acad Sci U S A. 2003;100:8963–8968. doi: 10.1073/pnas.1533420100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Guenther M G, Barak O, Lazar M A. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol Cell Biol. 2001;21:6091–6101. doi: 10.1128/MCB.21.18.6091-6101.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Guise A J, Budayeva H G, Diner B A, Cristea I M. Histone deacetylases in herpesvirus replication and virus-stimulated host defense. Viruses. 2013;5:1607–1632. doi: 10.3390/v5071607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hagemeier C, Walker S M, Sissons P J, Sinclair J H. The 72K IE1 and 80K IE2 proteins of human cytomegalovirus independently trans-activate the c-fos, c-myc and hsp70 promoters via basal promoter elements. J Gen Virol. 1992;73:2385–2393. doi: 10.1099/0022-1317-73-9-2385. [DOI] [PubMed] [Google Scholar]
  25. Henry S C, Schmader K, Brown T T, Miller S E, Howell D N, Daley G G, Hamilton J D. Enhanced green fluorescent protein as a marker for localizing murine cytomegalovirus in acute and latent infection. J Virol Methods. 2000;89:61–73. doi: 10.1016/S0166-0934(00)00202-0. [DOI] [PubMed] [Google Scholar]
  26. Hensel G M, Meyer H H, Buchmann I, Pommerehne D, Schmolke S, Plachter B, Radsak K, Kern H F. Intracellular localization and expression of the human cytomegalovirus matrix phosphoprotein pp71 (ppUL82): evidence for its translocation into the nucleus. J Gen Virol. 1996;77:3087–3097. doi: 10.1099/0022-1317-77-12-3087. [DOI] [PubMed] [Google Scholar]
  27. Hofmann H, Sindre H, Stamminger T. Functional interaction between the pp71 protein of human cytomegalovirus and the PML-interacting protein human Daxx. J Virol. 2002;76:5769–5783. doi: 10.1128/JVI.76.11.5769-5783.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Homer E G, Rinaldi A, Nicholl M J, Preston C M. Activation of herpesvirus gene expression by the human cytomegalovirus protein pp71. J Virol. 1999;73:8512–8518. doi: 10.1128/jvi.73.10.8512-8518.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ishov A M, Vladimirova O V, Maul G G. Daxx-mediated accumulation of human cytomegalovirus tegument protein pp71 at ND10 facilitates initiation of viral infection at these nuclear domains. J Virol. 2002;76:7705–7712. doi: 10.1128/JVI.76.15.7705-7712.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ishov A M, Sotnikov A G, Negorev D, Vladimirova O V, Neff N, Kamitani T, Yeh E T, Strauss J F, 3rd, Maul G G. PML is critical for ND10 formation and recruits the PML-interacting protein Daxx to this nuclear structure when modified by SUMO-1. J Cell Biol. 1999;147:221–234. doi: 10.1083/jcb.147.2.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Jurak I, Brune W. Induction of apoptosis limits cytomegalovirus cross-species infection. EMBO J. 2006;25:2634–2642. doi: 10.1038/sj.emboj.7601133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Korioth F, Maul G G, Plachter B, Stamminger T, Frey J. The nuclear domain 10 (ND10) is disrupted by the human cytomegalovirus gene product IE1. Exp Cell Res. 1996;229:155–158. doi: 10.1006/excr.1996.0353. [DOI] [PubMed] [Google Scholar]
  33. Kurz S K, Reddehase M J. Patchwork pattern of transcriptional reactivation in the lungs indicates sequential checkpoints in the transition from murine cytomegalovirus latency to recurrence. J Virol. 1999;73:8612–8622. doi: 10.1128/jvi.73.10.8612-8622.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Lafemina R L, Hayward G S. Differences in cell-type-specific blocks to immediate early gene expression and DNA rep lication of human, simian and murine cytomegalovirus. J Gen Virol. 1988;69:355–374. doi: 10.1099/0022-1317-69-2-355. [DOI] [PubMed] [Google Scholar]
  35. Lashmit P E, Lundquist C A, Meier J L, Stinski M F. Cellular repressor inhibits human cytomegalovirus transcription from the UL127 promoter. J Virol. 2004;78:5113–5123. doi: 10.1128/JVI.78.10.5113-5123.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Lee H R, Ahn J H. Sumoylation of the major immediate-early IE2 protein of human cytomegalovirus Towne strain is not required for virus growth in cultured human fibroblasts. J Gen Virol. 2004;85:2149–2154. doi: 10.1099/vir.0.79954-0. [DOI] [PubMed] [Google Scholar]
  37. Liu B, Stinski M F. Human cytomegalovirus contains a tegument protein that enhances transcription from promoters with upstream ATF and AP-1 cis-acting elements. J Virol. 1992;66:4434–4444. doi: 10.1128/jvi.66.7.4434-4444.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Lundquist C A, Meier J L, Stinski M F. A strong negative transcriptional regulatory region between the human cytomegalovirus UL127 gene and the major immediate-early enhancer. J Virol. 1999;73:9039–9052. doi: 10.1128/jvi.73.11.9039-9052.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Margolis M J, Pajovic S, Wong E L, Wade M, Jupp R, Nelson J A, Azizkhan J C. Interaction of the 72-kilodalton human cytomegalovirus IE1 gene product with E2F1 coincides with E2F-dependent activation of dihydrofolate reductase transcription. J Virol. 1995;69:7759–7767. doi: 10.1128/jvi.69.12.7759-7767.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Martinez F P, Cruz R, Lu F, Plasschaert R, Deng Z, Rivera-Molina Y A, Bartolomei M S, Lieberman P M, Tang Q. CTCF Binding to the First Intron of the Major Immediate-Early (MIE) Gene of Human Cytomegalovirus (HCMV) Negatively Regulates MIE Gene Expression and HCMV Replication. J Virol. 2014;88:7381–7401. doi: 10.1128/JVI.00845-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Meier J L. Reactivation of the human cytomegalovirus major immediate-early regulatory region and viral replication in embryonal NTera2 cells: role of trichostatin A, retinoic acid, and deletion of the 21-base-pair repeats and modulator. J Virol. 2001;75:1581–1593. doi: 10.1128/JVI.75.4.1581-1593.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Meier J L, Stinski M F. Regulation of human cytomegalovirus immediate-early gene expression. Intervirology. 1996;39:331–342. doi: 10.1159/000150504. [DOI] [PubMed] [Google Scholar]
  43. Meier J L, Pruessner J A. The human cytomegalovirus major immediate-early distal enhancer region is required for efficient viral replication and immediate-early gene expression. J Virol. 2000;74:1602–1613. doi: 10.1128/JVI.74.4.1602-1613.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Mocarski E S, Kemble G W, Lyle J M, Greaves R F. A deletion mutant in the human cytomegalovirus gene encoding IE1(491aa) is replication defective due to a failure in autoregulation. Proc Natl Acad Sci U S A. 1996;93:11321–11326. doi: 10.1073/pnas.93.21.11321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Mocarski E S, Jr., Shenk T, Pass R F. Cytomegaloviruses. 5th Edition ed. Philadelphia: Lippincott Williams & Wilkins; 2006. pp. 567–601. [Google Scholar]
  46. Netterwald J, Yang S, Wang W, Ghanny S, Cody M, Soteropoulos P, Tian B, Dunn W, Liu F, Zhu H. Two gamma interferon-activated site-like elements in the human cytomegalovirus major immediate-early promoter/enhancer are important for viral replication. J Virol. 2005;79:5035–5046. doi: 10.1128/JVI.79.8.5035-5046.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Nevels M, Paulus C, Shenk T. Human cytomegalovirus immediate-early 1 protein facilitates viral replication by antagonizing histone deacetylation. Proc Natl Acad Sci U S A. 2004;101:17234–17239. doi: 10.1073/pnas.0407933101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Perez K J, Martinez F P, Cosme-Cruz R, Perez-Crespo N M, Tang Q. A short cis-acting motif in the M112–113 promoter region is essential for IE3 to activate M112–113 gene expression and is important for murine cytomegalovirus replication. J Virol. 2013;87:2639–2647. doi: 10.1128/JVI.03171-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Pizzorno M C, Hayward G S. The IE2 gene products of human cytomegalovirus specifically down-regulate expression from the major immediate-early promoter through a target sequence located near the cap site. J Virol. 1990;64:6154–6165. doi: 10.1128/jvi.64.12.6154-6165.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Ramsay M E, Miller E, Peckham C S. Outcome of confirmed symptomatic congenital cytomegalovirus infection. Arch Dis Child. 1991;66:1068–1069. doi: 10.1136/adc.66.9.1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Reddehase M J, Podlech J, Grzimek N K. Mouse models of cytomegalovirus latency: overview. J Clin Virol. 2002;25(Suppl2):S23–S36. doi: 10.1016/S1386-6532(02)00087-2. [DOI] [PubMed] [Google Scholar]
  52. Reddehase M J, Simon C O, Podlech J, Holtappels R. Stalemating a clever opportunist: lessons from murine cytomegalovirus. Hum Immunol. 2004;65:446–455. doi: 10.1016/j.humimm.2004.02.024. [DOI] [PubMed] [Google Scholar]
  53. Revello M G, Gerna G. Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant. Clin Microbiol Rev. 2002;15:680–715. doi: 10.1128/CMR.15.4.680-715.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Revello M G, Zavattoni M, Furione M, Lilleri D, Gorini G, Gerna G. Diagnosis and outcome of preconceptional and periconceptional primary human cytomegalovirus infections. J Infect Dis. 2002;186:553–557. doi: 10.1086/341831. [DOI] [PubMed] [Google Scholar]
  55. Rivera-Molina Y A, Martinez F P, Tang Q. Nuclear domain 10 of the viral aspect. World J Virol. 2013;2:110–122. doi: 10.5501/wjv.v2.i3.110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Saffert R T, Kalejta R F. Inactivating a cellular intrinsic immune defense mediated by Daxx is the mechanism through which the human cytomegalovirus pp71 protein stimulates viral immediate-early gene expression. J Virol. 2006;80:3863–3871. doi: 10.1128/JVI.80.8.3863-3871.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Saffert R T, Kalejta R F. Promyelocytic leukemia-nuclear body proteins: herpesvirus enemies, accomplices, or both? Future Virol. 2008;3:265–277. doi: 10.2217/17460794.3.3.265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Smith J A, Pari G S. Expression of human cytomegalovirus UL36 and UL37 genes is required for viral DNA replication. J Virol. 1995;69:1925–1931. doi: 10.1128/jvi.69.3.1925-1931.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Stagno S, Pass R F, Cloud G, Britt W J, Henderson R E, Walton P D, Veren D A, Page F, Alford C A. Primary cytomegalovirus infection in pregnancy. Incidence, transmission to fetus, and clinical outcome. Jama. 1986;256:1904–1908. doi: 10.1001/jama.1986.03380140074025. [DOI] [PubMed] [Google Scholar]
  60. Stinski M F, Isomura H. Role of the cytomegalovirus major immediate early enhancer in acute infection and reactivation from latency. Med Microbiol Immunol. 2008;197:223–231. doi: 10.1007/s00430-007-0069-7. [DOI] [PubMed] [Google Scholar]
  61. Tang Q, Maul G G. Mouse Cytomegalovirus Immediate-Early Protein 1 Binds with Host Cell Repressors To Relieve Suppressive Effects on Viral Transcription and Replication during Lytic Infection. J Virol. 2003;77:1357–1367. doi: 10.1128/JVI.77.2.1357-1367.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Tang Q, Maul G G. Mouse cytomegalovirus crosses the species barrier with help from a few human cytomegalovirus proteins. J Virol. 2006;80:7510–7521. doi: 10.1128/JVI.00684-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Tang Q, Maul G G. Immediate early interactions and epigenetic defense mechanisms of cytomegaloviruses. In: Reddehase M J, Lemmermann N, editors. Cytomegaloviruses: Molecular Biology and Immunology. Wymondham: Caister Academic Press; 2006. pp. 230–268. [Google Scholar]
  64. Tang Q, Murphy E A, Maul G G. Experimental confirmation of global murine cytomegalovirus open reading frames by transcriptional detection and partial characterization of newly described gene products. J Virol. 2006;80:6873–6882. doi: 10.1128/JVI.00275-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Tavalai N, Stamminger T. Interplay between Herpesvirus Infection and Host Defense by PML Nuclear Bodies. Viruses. 2009;1:1240–1264. doi: 10.3390/v1031240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Tavalai N, Papior P, Rechter S, Leis M, Stamminger T. Evidence for a role of the cellular ND10 protein PML in mediating intrinsic immunity against human cytomegalovirus infections. J Virol. 2006;80:8006–8018. doi: 10.1128/JVI.00743-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Tavalai N, Adler M, Scherer M, Riedl Y, Stamminger T. Evidence for a dual antiviral role of the major nuclear domain 10 component Sp100 during the immediate-early and late phases of the human cytomegalovirus replication cycle. J Virol. 2011;85:9447–9458. doi: 10.1128/JVI.00870-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Yang S, Netterwald J, Wang W, Zhu H. Characterization of the elements and proteins responsible for interferon-stimulated gene induction by human cytomegalovirus. J Virol. 2005;79:5027–5034. doi: 10.1128/JVI.79.8.5027-5034.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Virologica Sinica are provided here courtesy of Wuhan Institute of Virology, Chinese Academy of Sciences

RESOURCES