Abstract
The history of the molecular biology of cytomegaloviruses from the purification of the virus and the viral DNA to the cloning and expression of the viral genes is reviewed. A key genetic element of cytomegalovirus (the CMV promoter) contributed to our understanding of eukaryotic cell molecular biology and to the development of lifesaving therapeutic proteins. The study of the molecular biology of cytomegaloviruses also contributed to the development of antivirals to control the viral infection.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Ho M (1991) Cytomegalovirus: biology and infection, 2nd edn. Plenum Publishing Corp, New York
Alford CA, Britt WJ (1990) Cytomegalovirus. In: Fields BN, Knipe DM et al (eds) Virology. Raven Press Ltd, New York, pp 1981–2010
Stinski MF (1976) Human cytomegalovirus: glycoproteins associated with virions and dense bodies. J Virol 19:594–609
Stinski MF (1977) Synthesis of proteins and glycoproteins in cells infected with human cytomegalovirus. J Virol 23:751–767
Stinski MF (1978) Sequence of protein synthesis in cells infected by human cytomegalovirus: early and late virus-induced polypeptides. J Virol 26:686–701
Huang E-S, Chen S-T, Pagano JS (1973) Human cytomegalovirus. I. Purification and characterization of viral DNA. J Virol 12:1473–1481
Sarov I, Friedman A (1976) Electron microscopy of human cytomegalovirus DNA. Arch Virol 50:343–347
Kilpatrick BA, Huang ES (1977) Human cytomegalovirus genome: partial denaturation map and organization of genome sequences. J Virol 24:261–276
DeMarchi JM, Blankship ML, Brown GD, Kaplan AS (1978) Size and complexity of human cytomegalovirus DNA. Virology 89:643–646
Geelen JLMC, Walig C, Wertheim P, Van der Noordaa J (1978) Human cytomegalovirus DNA. I. Molecular weight and infectivity. J Virol 26:813–816
Stinski MF, Mocarski ES, Thomsen DR (1979) DNA of human cytomegalovirus: size heterogeneity and defectiveness resulting from serial undiluted passage. J Virol 31:231–239
Tamashiro JC, Spector DH (1980) Molecular cloning of the human cytomegalovirus genome (strain AD169). In: Fields BN, Jaenisch R (eds) Animal virus genetics. Academic, New York, pp 21–37
Thomsen DR, Stinski MF (1981) Cloning of the human cytomegalovirus genome as endonuclease XbaI fragments. Gene 16:207–216
Fleckenstein B, Muller I, Collins J (1982) Cloning of the complete human cytomegalovirus genome in cosmids. Gene 18:39–46
DeMarchi JM, Schmidt CA, Kaplan AS (1980) Patterns of transcription of human cytomegalovirus in permissively infected cells. J Virol 35:277–286
LaFemina RL, Hayward GS (1980) Structural organization of the DNA molecules from human cytomegalovirus. In: Fields BN, Jaenisch R (eds) Animal virus genetics. Academic, New York, pp 39–55
Weststrate MW, Geelen JLMC, Van der Noordaa J (1980) Human cytomegalovirus DNA: physical maps for the restriction endonuclease BgIII, HindIII, and XbaI. J Gen Virol 49:1–21
Wathen MW, Thomsen DR, Stinski MF (1981) Temporal regulation of human cytomegalovirus transcription at immediate-early and early times after infection. J Virol 38: 446–459
DeMarchi JM (1981) Human cytomegalovirus DNA: restriction enzyme cleavage maps and map location for immediate-early, early, and late RNAs. Virology 124:390–402
Stinski MF (1990) Cytomegalovirus and its replication. In: Knipe DM et al (eds) Virology, 2nd edn. Raven, New York, pp 1959–1980
Wathen MW, Stinski MF (1982) Temporal patterns of human cytomegalovirus transcription: mapping the viral RNAs synthesized at immediate early, early, and late times after infection. J Virol 41:462–477
Stinski MF, Thomsen DR, Wathen MW (1981) Structure and function of the cytomegalovirus genome. In: Nahmias A, Dowdle WR, Schinazi RF (eds) The human herpesviruses: an interdisciplinary perspective. Elsevier, New York, pp 72–84
Stinski MF, Thomsen DR, Stenberg RM, Goldstein LC (1983) Organization and expression of the immediate early genes of human cytomegalovirus. J Virol 46:1–14
Stenberg RM, Thomsen DR, Stinski MF (1984) Structural analysis of the major immediate early gene of human cytomegalovirus. J Virol 49:190–199
Stenberg RM, Witte PR, Stinski MF (1985) Multiple spliced and unspliced transcripts from human cytomegalovirus immediate-early region 2 and evidence for a common initiation site within immediate-early region 1. J Virol 56:665–675
Stinski MF, Stenberg RM, Goins WF (1984) Structure and function of the human cytomegalovirus immediate early genes. In: Rapp F (ed) Herpesvirus. Alan R. Liss, Inc., New York, pp 399–421
Stinski MF (1984) The proteins of human cytomegalovirus. In: Plotkin SA, Michelson S, Pagano JS, Rapp F (eds) CMV pathogenesis and prevention of human infection. Alan R. Liss, Inc., New York, pp 49–62
Thomsen DR, Stenberg RM, Goins WF, Stinski MF (1984) Promoter-regulatory region of the major immediate early gene of human cytomegalovirus. Proc Natl Acad Sci USA 81:659–663
Boshart M, Weber F, Jahn G, Dorsch-Hasler K, Fleckenstein B, Schaffner W (1985) A very strong enhancer is located upstream of an immediate early gene of human cytomegalovirus. Cell 41:521–530
Stinski MF, Roehr TJ (1985) Activation of the major immediate early gene of human cytomegalovirus by cis-acting elements in the promoter-regulatory sequence and by virus-specific trans-acting components. J Virol 55:431–441
Stinski MF (1999) Cytomegalovirus promoter for expression in mammalian cells. In: Ferandez JM, Hoeffler JP (eds) Gene expression systems: using nature for the art of expression. Academic, San Diego, CA, pp 211–233
Chee MA, Bankier AT, Beck S, Bohni R, Brown CM, Cerny R et al (1990) Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169. Curr Top Microbiol Immunol 154:125–169
Murphy E, Dong Y, Grimwood J, Schmutz J, Dickson M, Jarvis MA et al (2003) Coding potential of laboratory and clinical stains of human cytomegalovirus. Proc Natl Acad Sci USA 100:14976–14981
Murphy E, Rigoutsos I, Shibuya T, Shenk T (2003) Reevaluation of human cytomegalovirus coding potential. Proc Natl Acad Sci USA 100:13585–13590
Dunn W, Chou C, Hong L, Hai R, Patterson D, Stolc V et al (2003) Functional profiling of a human cytomegalovirus genome. Proc Natl Acad Sci USA 100:14223–14228
Gatherer D, Seirafian S, Cunningham C, Holton M, Dargan DJ, Baluchova K et al (2011) High-resolution human cytomegalovirus transcriptome. Proc Natl Acad Sci USA 108:19755–19760
Hamzeh FM, Lietman PS, Gibson W, Hayward GS (1990) Identification of the lytic origin of DNA replication in human cytomegalovirus by a novel approach utilizing ganciclovir-induced chain termination. J Virol 64:6184–6195
Pari GS, Anders DG (1993) Eleven loci encoding trans-acting factors are required for transient complementation of human cytomegalovirus oriLyt-dependent DNA replication. J Virol 67: 6979–6988
Zhu Y, Huang L, Anders DG (1998) Human cytomegalovirus oriLyt sequence requirements. J Virol 72:4989–4996
Sarisky RT, Hayward GS (1996) Evidence that the UL84 gene product of human cytomegalovirus is essential for promoting oriLyt-dependent DNA replication and formation of replication compartments in cotransfection assays. J Virol 70:7398–7413
Xu Y, Cei SA, Rodriguez HA, 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
Pari GS (2008) Nuts and bolts of human cytomegalovirus lytic DNA replication. In: Shenk T, Stinski MF (eds) Human cytomegalovirus, Current topics in microbiology and immunology. Springer, Berlin, pp 153–166
Prichard MN, Jairath S, Penfold MET, St. Jeor S, Bohlman MC, Pari GS (1998) Identification of persistent RNA-DNA hybrid structures within the origin of replication of human cytomegalovirus. J Virol 72:6997–7004
Hermiston TW, Malone CL, Witte PR, Stinski MF (1987) Identification and characterization of the human cytomegalovirus immediate-early region 2 gene that stimulates gene expression from an inducible promoter. J Virol 61:3214–3221
Tevethia MJ, Spector DJ, Leisure KM, Stinski MF (1987) Participation of two human cytomegalovirus immediate early gene regions in transcriptional activation of adenovirus promoters. Virology 161(2):276–285
Stinski MF, Malone CL, Hermiston TW, Liu B (1991) Regulation of human cytomegalovirus transcription. In: Wagner EK (ed) Herpesvirus transcription and its control. CRC Press, Boca Raton, FL, pp 245–260
Stinski MF (1991) Molecular biology of cytomegalovirus replication. In: Ho M (ed) Cytomegalovirus biology and infection, 2nd edn. Plenum Medical Book Co., New York, pp 7–36
Stinski MF, Macias MP, Malone CL, Thrower AR, Huang L (1993) Regulation of transcription from the cytomegalovirus major immediate early promoter by cellular and viral proteins. In: Michelson S, Plotkin SA (eds) Multidisciplinary approach to understanding cytomegalovirus. Elsevier Science, Amsterdam, pp 3–12
Maul GG (2008) Initiation of cytomegalovirus infection at ND10. In: Shenk T, Stinski MF (eds) Human cytomegalovirus, Current topics in microbiology and immunology. Springer, Berlin, pp 117–132
Tavalai N, Papior P, Rechter S, Stamminger T (2008) Nuclear domain 10 components promyelocytic leukemia protein and hDaxx independently contribute to an intrinsic antiviral defense against human cytomegalovirus infection. J Virol 82:126–137
Huh YH, Kim YE, Kim ET, Park JJ, Song MJ, Zhu H, Hayward GS, Ahn J-H (2008) Binding STAT2 by the acidic domain of human cytomegalovirus IE1 promotes viral growth and is negatively regulated by SUMO. J Virol 82:10444–10454
Castillo JP, Yurochko AD, Kowalik TF (2000) Role of human cytomegalovirus immediate-early proteins in cell growth control. J Virol 74:8028–8037
Yee L-F, Lin PL, Stinski MF (2007) Ectopic expression of HCMV IE72 and IE86 proteins is sufficient to induce early gene expression but not production of infectious virus in undifferentiated promonocytic THP-1 cells. Virology 363:174–188
Greaves RF, Brown JM, Vieira J, Mocarski ES (1995) Selectable insertion and deletion mutagenesis of the human cytomegalovirus genome using the E. coli guanosine phosphoribosyl transferase (gpt) gene. J Gen Virol 76: 2151–2160
Greaves RF, Mocarski ES (1998) Defective growth correlates with reduced accumulation of viral DNA replication protein after low-multiplicity infection by a human cytomegalovirus ie1 mutant. J Virol 72:366–379
Meier JL, Stinski MF (1997) Effect of a modulator deletion on transcription of the human cytomegalovirus major immediate-early genes in infected undifferentiated and differentiated cells. J Virol 71:1246–1255
Messerle M, Crnkovic I, Hammerschmidt W, Ziegler H, Koszinowski UU (1997) Cloning and mutagenesis of a herpesvirus genome as an infectious bacterial artificial chromosome. Proc Natl Acad Sci USA 94:14759–14763
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
Marchini A, Liu H, Ahu H (2001) Human cytomegalovirus with IE-2 (UL122) deleted fails to express early lytic genes. J Virol 75:1870–1878
Angulo A, Messerle M, Koszinowski UH, Ghazal P (1998) Enhancer requirement for murine cytomegalovirus growth and genetic complementation by the human cytomegalovirus enhancer. J Virol 72:8502–8509
Isomura H, Stinski MF (2003) Effect of substitution of the human cytomegalovirus enhancer or promoter with the murine cytomegalovirus enhancer or promoter on replication in human fibroblast. J Virol 77:3602–3614
Meier JL, Pruessner JA (2000) The human cytomegalovirus major immediate-early distal enhancer region is required for efficient viral replication and immediate-early expression. J Virol 74:1602–1613
Isomura H, Tatsuya T, Stinski MF (2004) The role of the proximal enhancer of the major immediate early promoter in human cytomegalovirus replication. J Virol 78:12788–12799
Isomura H, Stinski MF, Kudoh A, Daikoku T, Shirata N, Tsurumi T (2005) Two Sp1/Sp3 binding sites in the major immediate-early proximal enhancer of human cytomegalovirus have a significant role in viral replication. J Virol 79:9597–9607
Lashmit P, Wang S, Li H, Isomura H, Stinski MF (2009) The CREB site in the proximal enhancer is critical for cooperative interaction with the other transcription factor binding sites to enhance transcription of the major intermediate-early genes in human cytomegalovirus-infected cells. J Virol 83: 8893–8904
Stinski MF, Meier JL (2007) Immediate-early viral gene regulation and function. In: Arvin A et al (eds) Human herpesviruses biology, therapy, and immunoprophylaxis. Cambridge University Press, New York, pp 241–263
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, Norfolk, UK, pp 151–166
Stinski MF, Isomura H (2008) Role of the cytomegalovirus major immediate early enhancer in acute infection and reactivation from latency. Med Microbiol Immunol 197: 223–231
Dittmer D, Mocarski ES (1997) Human cytomegalovirus infection inhibits G1/S transition. J Virol 71:1629–1634
Jault FM, Jault J-M, Ruchti F, Fortunato EA, Clark C, Corbeil J et al (1995) Cytomegalovirus infection induces high levels of cyclins, phosphorylated RB, and p53, leading to cell cycle arrest. J Virol 69:6697–6704
Lu M, Shenk T (1996) Human cytomegalovirus infection inhibits cell cycle progression at multiple points including the transition from G1 to S. J Virol 70:8850–8857
Salvant BS, Fortunato EA, Spector DH (1998) Cell cycle dysregulation by human cytomegalovirus: influence of the cell cycle phase at the time of infection and effects on cyclin transcription. J Virol 72:3729–3741
Fortunato E, Sanchez V, Yen JY, Spector DH (2002) Infection of cells with human cytomegalovirus during S phase results in a blockade to immediate-early gene expression that can be overcome by inhibition of the proteasome. J Virol 76:5369–5379
Zydek M, Hagemeier C, Wiebusch L (2010) Cyclin-dependent kinase activity controls the onset of the HCMV lytic cycle. PLoS Pathog 6:1–16
Du G, Dutta N, Lashmit P, Stinski MF (2011) Alternative splicing of the human cytomegalovirus major immediate-early genes affects infectious-virus replication and control of cellular cyclin-dependent kinase. J Virol 85:804–817
Luo MH, Rosenke K, Czornak K, Fortunato EA (2007) Human cytomegalovirus disrupts both ataxia telangiectasia mutated protein (ATM)- and ATM-Rad3-related kinase-mediated DNA damage responses during lytic infection. J Virol 81:1934–1950
Hannemann H, Rosenki K, O’Dowd JM, Fortunato EA (2009) The presence of p53 influences the expression of multiple human cytomegalovirus genes at early times postinfection. J Virol 83:4316–4325
Tsai HL, Kou GH, Chen SC, Wu CW, Lin YS (1996) Human cytomegalovirus immediate-early protein IE2 tethers a transcriptional repression domain to p53. J Biol Chem 271:3534–3540
Stinski MF, Petrik DT (2008) Functional roles of the human cytomegalovirus essential IE86 protein. In: Shenk T, Stinski MF (eds) Human cytomegalovirus, Current topics in microbiology and immunology. Springer, Berlin, pp 133–152
Song Y-J, Stinski MF (2002) Effect of the human cytomegalovirus IE86 protein on expression of E2F-responsive genes: a DNA microarray analysis. Proc Natl Acad Sci USA 99:2836–2841
Song Y-J, Stinski MF (2004) Inhibition of cell division by the human cytomegalovirus IE86 protein: role of the p53 pathway or cdk1/cyclin B1. J Virol 79:2597–2603
Hume AJ, Finkel JS, Kamil JP, Coen DM, Culbertson MR, Kalejta RF (2008) Phosphorylation of retinoblastoma protein by viral protein with cyclin-dependent kinase function. Science 320:797–799
Qian Z, Leung-Pineda V, Xuan B, Piwnica-Worms H, Yu D (2010) Human cytomegalovirus protein pUL117 targets the mini-chromosome maintenance complex and suppresses cellar DNA synthesis. PLoS Pathog 6:e1000814
Wiebusch L, Neuwirth A, Grabenhenrich L, Voight S, Hagemeier C (2008) Cell cycle-independent expression of immediate-early gene 3 results in G1 and G2 arrest in murine cytomegalovirus-infected cells. J Virol 82: 10188–10198
Isomura H, Stinski MF, Murata T, Yamashita Y, Kanda T, Toyokuni S et al (2011) The human cytomegalovirus gene products essential for late viral gene expression assemble into prereplication complexes before viral DNA replication. J Virol 85:6629–6644
Perng Y-C, Qian Z, Fehr AR, Xuan B, Yu D (2011) The human cytomegalovirus gene UL79 is required for the accumulation of late viral transcripts. J Virol 85:4841–4852
Acknowledgments
The author regrets not acknowledging all important details and contributions over the last 40 years within the page limitation. The author thanks the National Institutes of Health and the many colleagues and friends for their support.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this protocol
Cite this protocol
Stinski, M.F. (2014). History of the Molecular Biology of Cytomegaloviruses. In: Yurochko, A., Miller, W. (eds) Human Cytomegaloviruses. Methods in Molecular Biology, vol 1119. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-788-4_1
Download citation
DOI: https://doi.org/10.1007/978-1-62703-788-4_1
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-62703-787-7
Online ISBN: 978-1-62703-788-4
eBook Packages: Springer Protocols