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Murine Model of Cytomegalovirus Latency and Reactivation

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Human Cytomegalovirus

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 325))

Efficient resolution of acute cytopathogenic cytomegalovirus infection through innate and adaptive host immune mechanisms is followed by lifelong maintenance of the viral genome in host tissues in a state of replicative latency, which is interrupted by episodes of virus reactivation for transmission. The establishment of latency is the result of aeons of co-evolution of cytomegaloviruses and their respective host species. Genetic adaptation of a particular cytomegalovirus to its specific host is reflected by private gene families not found in other members of the cytomegalovirus group, whereas basic functions of the viral replicative cycle are encoded by public gene families shared between different cytomegaloviruses or even with herpesviruses in general. Private genes include genes coding for immunoevasins, a group of glycoproteins specifically dedicated to dampen recognition by the host’s innate and adaptive immune surveillance to protect the virus against elimination. Recent data in the mouse model of cytomegalovirus latency have indicated that viral replicative latency established in the immunocompetent host is a dynamic state characterized by episodes of viral gene desilencing and immune sensing of reactivated presentation of antigenic peptides at immunological checkpoints by CD8 T cells. This sensing maintains viral replicative latency by triggering antiviral effector functions that terminate the viral gene expression program before infectious viral progeny are assembled. According to the immune sensing hypothesis of latency control, immunological checkpoints are unique for each infected individual in reflection of host MHC (HLA) polymorphism and the proteome(s) of the viral variant(s) harbored in latency.

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References

  • Adachi N, Lieber MR (2002) Bidirectional gene organization: a common architectural feature of the human genome. Cell 109:807–809.

    Article  PubMed  CAS  Google Scholar 

  • Angulo A, Ghazal P, Messerle M (2000) The major immediate-early gene ie3 of mouse cytomegalovirus is essential for viral growth. J Virol 74:11129–11136.

    Article  PubMed  CAS  Google Scholar 

  • Bain M, Reeves M, Sinclair J (2006) Regulation of human cytomegalovirus gene expression by chromatin remodeling. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Wymondham, Norfolk, pp 167–183.

    Google Scholar 

  • Balthesen M, Messerle M, Reddehase MJ (1993) Lungs are a major organ site of cytomegalovirus latency and recurrence. J Virol 67:5360–5366.

    PubMed  CAS  Google Scholar 

  • Benedict CA, Angulo A, Patterson G, Ha S, Huang A, Messerle M, Ware CF, Ghazal P (2004) Neutrality of the canonical NF-kappaB-dependent pathway for human and murine cytomegalovirus transcription and replication in vitro. J Virol 78:741–750.

    Article  PubMed  CAS  Google Scholar 

  • Bevan IS, Sammons CC, Sweet C (1996) Investigation of murine cytomegalovirus latency and reactivation in mice using viral mutants and the polymerase chain reaction. J Med Virol 48:308–320.

    Article  PubMed  CAS  Google Scholar 

  • Brune W, Wagner M, Messerle M (2006) Manipulating cytomegalovirus genomes by BAC mutagenesis: strategies and applications. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Wymondham, Norfolk, pp 63–89.

    Google Scholar 

  • Cardin RD, Abenes GB, Stoddard CA, Mocarski ES (1995) Murine cytomegalovirus IE2, an activator of gene expression, is dispensable for growth and latency in mice. Virology 209:236–241.

    Article  PubMed  CAS  Google Scholar 

  • Cavanaugh VJ, Deng Y, Birkenbach MP, Slater JS, Campbell AE (2003) Vigorous innate and virus-specific cytotoxic T-lymphocyte responses to murine cytomegalovirus in the submaxillary salivary gland. J Virol 77:1703–1717.

    Article  PubMed  CAS  Google Scholar 

  • Chatellard P, Pankiewicz R, Meier E, Durrer L, Sauvage C, Imhof MO (2007) The IE2 promoter/enhancer region from mouse CMV provides high levels of therapeutic protein expression in mammalian cells. Biotechnol Bioeng 96:106–117.

    Article  PubMed  CAS  Google Scholar 

  • Cook CH, Zhang Y, McGuinness BJ, Lahm MC, Sedmak DD, Ferguson RM (2002) Intra-abdominal bacterial infection reactivates latent pulmonary cytomegalovirus in immunocompetent mice. J Infect Dis 185:1395–1400.

    Article  PubMed  Google Scholar 

  • Cook CH, Trgovcich J, Zimmermann PD, Zhang Y, Sedmak DD (2006) Lipopolysaccharide, tumor necrosis factor alpha, or interleukin-1beta triggers reactivation of latent cytomegalovirus in immunocompetent mice. J Virol 80:9151–9158.

    Article  PubMed  CAS  Google Scholar 

  • Davis-Poynter NJ, Lynch DM, Vally H, Shellam GR, Rawlinson WD, Barrell BG, Farrell HE (1997) Identification and characterization of a G protein-coupled receptor homolog encoded by murine cytomegalovirus. J Virol 71:1521–1529.

    PubMed  CAS  Google Scholar 

  • Dorsch-Häsler K, Keil GM, Weber F, Jasin M, Schaffner W, Koszinowski UH (1985) A long and complex enhancer activates transcription of the gene coding for the highly abundant immediate early mRNA in murine cytomegalovirus. Proc Natl Acad Sci U S A 82:8325–8329.

    Article  PubMed  Google Scholar 

  • Fiering S, Whitelaw E, Martin DIK (2000) To be or not to be active: the stochastic nature of enhancer action. BioEssays 22:381–387.

    Article  PubMed  CAS  Google Scholar 

  • Ghazal P, Messerle M, Osborn K, Angulo A (2003) An essential role of the enhancer for murine cytomegalovirus in vivo growth and pathogenesis. J Virol 77:3217–3228.

    Article  PubMed  CAS  Google Scholar 

  • Gribaudo G, Riera L, Lembo D, De Andrea M, Gariglio M, Rudge TL, Johnson LF, Landolfo S (2000) Murine cytomegalovirus stimulates cellular thymidylate synthase gene expression in quiescent cells and requires the enzyme for replication. J Virol 74:4979–4987.

    Article  PubMed  CAS  Google Scholar 

  • Grzimek NKA, Dreis D, Schmalz S, Reddehase MJ (2001) 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 75:2692–2705.

    Article  PubMed  CAS  Google Scholar 

  • Holtappels R, Pahl-Seibert MF, Thomas D, Reddehase MJ (2000) Enrichment of immediate-early 1 (m123/pp89) peptide-specific CD8 T-cells in a pulmonary CD62Llo memory-effector cell pool during latent murine cytomegalovirus infection of the lungs. J Virol 74:11495–11503.

    Article  PubMed  CAS  Google Scholar 

  • Holtappels R, Thomas D, Podlech J, Reddehase MJ (2002) Two antigenic peptides from genes m123 and m164 of murine cytomegalovirus quantitatively dominate CD8 T-cell memory in the H-2 d haplotype. J Virol 76:151–164.

    Article  PubMed  CAS  Google Scholar 

  • Hummel M, Abecassis MM (2002) A model for reactivation of CMV from latency. J Clin Virol 25:S123–S136.

    Article  PubMed  Google Scholar 

  • Hummel M, Zhang Z, Yan S, Deplaen I, Golia P, Varghese T, Thomas G, Abecassis MI (2001) Allogeneic transplantation induces expression of cytomegalovirus immediate-early genes in vivo: a model for reactivation from latency. J Virol 75:4814–4822.

    Article  PubMed  CAS  Google Scholar 

  • Hummel M, Yan S, Li Z, Varghese TK, Abecassis M (2007) 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 88:1097–1102.

    Article  PubMed  CAS  Google Scholar 

  • Humphreys IR, de Trez C, Kinkade A, Benedict CA, Croft M, Ware CF (2007) Cytomegalovirus exploits IL-10-mediated immune regulation in the salivary glands. J Exp Med 204:1217–1225.

    Article  PubMed  CAS  Google Scholar 

  • Ishiwata M, Baba S, Kawashima M, Kosugi I, Kawasaki H, Kaneta M, Tsuchida T, Kozuma S, Tsutsui Y (2006) Differential expression of the immediate-early 2 and 3 proteins in developing mouse brains infected with murine cytomegalovirus. Arch Virol 151:2181–2196.

    Article  PubMed  CAS  Google Scholar 

  • Jonjic S, Mutter W, Weiland F, Reddehase MJ, Koszinowski UH (1989) Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T-lymphocytes. J Exp Med 169:1199–1212.

    Article  PubMed  CAS  Google Scholar 

  • Jordan MC (1983) Latent infection and the elusive cytomegalovirus. Rev Infect Dis 5:205–215.

    PubMed  CAS  Google Scholar 

  • Kulesza CA, Shenk T (2006) Murine cytomegalovirus encodes a stable intron that facilitates persistent replication in the mouse. Proc Natl Acad Sci U S A 103:18302–18307.

    Article  PubMed  CAS  Google Scholar 

  • Kurz SK, Reddehase MJ (1999) Patchwork pattern of transcriptional reactivation in the lungs indicates sequential checkpoints in the transition from murine cytomegalovirus latency to recurrence. 73:8612–8622.

    Google Scholar 

  • Kurz SK, Steffens HP, Mayer A, Harris JR, Reddehase MJ (1997) Latency versus persistence or intermittent recurrences: evidence for a latent state of murine cytomegalovirus in the lungs. J Virol 71:2980–2987.

    PubMed  CAS  Google Scholar 

  • Kurz SK, Rapp M, Steffens HP, Grzimek NKA, Schmalz S, Reddehase MJ (1999) Focal transcriptional activity of murine cytomegalovirus during latency in the lungs. J Virol 73:482–494.

    PubMed  CAS  Google Scholar 

  • Lagenaur LA, Manning WC, Vieira J, Martens CL, Mocarski ES (1994) Structure and function of the murine cytomegalovirus sgg1 gene: a determinant of viral growth in salivary gland acinar cells. J Virol 68:7717–7727.

    PubMed  CAS  Google Scholar 

  • Lembo D, Gribaudo G, Hofer A, Riera L, Cornaglia M, Mondo A, Angeretti A, Gariglio M, Thelander L, Landolfo S (2000) Expression of an altered ribonucleotide reductase activity associated with the replication of murine cytomegalovirus in quiescent fibroblasts. J Virol 74:11557–11565.

    Article  PubMed  CAS  Google Scholar 

  • Li YY, Yu H, Guo ZM, Guo TQ, Tu K, Li YX (2006) Systematic analysis of head-to-head gene organization: evolutionary conservation and potential biological relevance. PLoS Comput Biol 2(7):e74 doi:10.1371/journal.pcbi.0020074.

    Article  PubMed  Google Scholar 

  • Meier JL, Stinski MF (2006) Major immediate-early enhancer and its gene products. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Wymondham, Norfolk, pp 151–166.

    Google Scholar 

  • Messerle M, Keil GM, Koszinowski UH (1991) Structure and expression of murine cytomegalovirus immediate-early gene 2. J Virol 65:1638–1643.

    PubMed  CAS  Google Scholar 

  • Polic B, Hengel H, Krmpotic A, Trgovcich J, Pavic I, Lucin P, Jonjic S, Koszinowski UH (1998) Hierarchical and redundant T-lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med 188:1047–1054.

    Article  PubMed  CAS  Google Scholar 

  • Pollock JL, Virgin HW IV (1995) Latency, without persistence, of murine cytomegalovirus in the spleen and kidney. J Virol 69:1762–1768.

    PubMed  CAS  Google Scholar 

  • Prösch S, Staak K, Stein J, Liebenthal C, Stamminger T, Volk HD, KrĂ¼ger DH (1995) Stimulation of the human cytomegalovirus IE enhancer/promoter in HL-60 cells by TNFalpha is mediated via induction of NF-kappaB. Virology 208:197–206.

    Article  PubMed  Google Scholar 

  • Rawlinson WD, Farrell HE, Barrell BG (1996) Analysis of the complete DNA sequence of murine cytomegalovirus. J Virol 70:8833–8849.

    PubMed  CAS  Google Scholar 

  • Reddehase MJ (2002) Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. Nat Immunol 2:831–844.

    Article  CAS  Google Scholar 

  • Reddehase MJ, Balthesen M, Rapp M, Jonjic S, Pavic I, Koszinowski UH (1994) The conditions of primary infection define the load of latent viral genome in organs and the risk of recurrent cytomegalovirus disease. J Exp Med 179:185–193.

    Article  PubMed  CAS  Google Scholar 

  • Reddehase MJ, Podlech J, Grzimek NKA (2002) Mouse models of cytomegalovirus latency: overview. J Clin Virol 25:S23–S36.

    Article  PubMed  CAS  Google Scholar 

  • Simon CO, Seckert CK, Dreis D, Reddehase MJ, Grzimek NKA (2005) Role for tumor necrosis factor alpha in murine cytomegalovirus transcriptional reactivation in latently infected lungs. J Virol 79:326–340.

    Article  PubMed  CAS  Google Scholar 

  • Simon CO, Holtappels R, Tervo HM, Böhm V, Däubner T, Oehrlein-Karpi SA, KĂ¼hnapfel B, Renzaho A, Strand D, Podlech J, Reddehase MJ, Grzimek NKA (2006a) CD8 T cells control cytomegalovirus latency by epitope-specific sensing of transcriptional reactivation. J Virol 80:10436–10456.

    Article  PubMed  CAS  Google Scholar 

  • Simon CO, Seckert CK, Grzimek NKA, Reddehase MJ (2006b) Murine model of cytomegalovirus latency and reactivation: the silencing/desilencing and immune sensing hypothesis. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Wymondham, Norfolk, pp 483–500.

    Google Scholar 

  • Simon CO, KĂ¼hnapfel B, Reddehase MJ, Grzimek NKA (2007) Murine cytomegalovirus major immediate early enhancer region operating as a genetic switch in bidirectional gene pair transcription. J Virol 81:7805–7810.

    Article  PubMed  CAS  Google Scholar 

  • Steffens HP, Kurz S, Holtappels R, Reddehase MJ (1998) Preemptive CD8 T-cell immunotherapy of acute cytomegalovirus infection prevents lethal disease, limits the burden of latent viral genomes, and reduces the risk of virus recurrence. J Virol 72:1797–1804.

    PubMed  CAS  Google Scholar 

  • Tang Q, Maul GG (2006) Immediate-early interactions and epigenetic defense mechanisms. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Wymondham, Norfolk, pp 131–149.

    Google Scholar 

  • Trinklein ND, Aldred SF, Hartman SJ, Schroeder DL, Otillar RP, Myers RM (2004) An abundance of bidirectional promoters in the human genome. Genome Res 14:62–66.

    Article  PubMed  CAS  Google Scholar 

  • Xiao J, Tong T, Zhan X, Haghjoo E, Liu F (2000) In vitro and in vivo characterization of a murine cytomegalovirus with a transposon insertional mutation at open reading frame M43. J Virol 74:9488–9497.

    Article  PubMed  CAS  Google Scholar 

  • Xu Y, Cei SA, Rodriguez Huete A, Colletti KS, Pari GS (2004) Human cytomegalovirus DNA replication requires transcriptional activation via an IE2-and UL84-responsive bidirectional promoter element within oriLyt. J Virol 78:11664–11677.

    Article  PubMed  CAS  Google Scholar 

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Reddehase, M.J., Simon, C.O., Seckert, C.K., Lemmermann, N., Grzimek, N.K.A. (2008). Murine Model of Cytomegalovirus Latency and Reactivation. In: Shenk, T.E., Stinski, M.F. (eds) Human Cytomegalovirus. Current Topics in Microbiology and Immunology, vol 325. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-77349-8_18

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