Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Virology Journal
Published in: Virology Journal 1/2009

Open Access 01-12-2009 | Short report

Conserved retinoblastoma protein-binding motif in human cytomegalovirus UL97 kinase minimally impacts viral replication but affects susceptibility to maribavir

Authors: Rachel B Gill, Samuel L Frederick, Caroll B Hartline, Sunwen Chou, Mark N Prichard

Published in: Virology Journal | Issue 1/2009

Login to get access

Abstract

The UL97 kinase has been shown to phosphorylate and inactivate the retinoblastoma protein (Rb) and has three consensus Rb-binding motifs that might contribute to this activity. Recombinant viruses containing mutations in the Rb-binding motifs generally replicated well in human foreskin fibroblasts with only a slight delay in replication kinetics. Their susceptibility to the specific UL97 kinase inhibitor, maribavir, was also examined. Mutation of the amino terminal motif, which is involved in the inactivation of Rb, also renders the virus hypersensitive to the drug and suggests that the motif may play a role in its mechanism of action.
Appendix
Available only for authorised users
Literature
1.
2.
Boppana SB, Fowler KB, Pass RF, Rivera LB, Bradford RD, Lakeman FD, Britt WJ: Congenital cytomegalovirus infection: association between virus burden in infancy and hearing loss. J Pediatr 2005, 146: 817-823. 10.1016/j.jpeds.2005.01.059CrossRefPubMed
3.
Fowler KB, Boppana SB: Congenital cytomegalovirus (CMV) infection and hearing deficit. J Clin Virol 2006, 35: 226-231. 10.1016/j.jcv.2005.09.016CrossRefPubMed
4.
Biron KK: Antiviral drugs for cytomegalovirus diseases. Antiviral Res 2006, 71: 154-163. 10.1016/j.antiviral.2006.05.002CrossRefPubMed
5.
Biron KK, Harvey RJ, Chamberlain SC, Good SS, Smith AA 3rd, Davis MG, Talarico CL, Miller WH, Ferris R, Dornsife RE, et al.: Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action. Antimicrob Agents Chemother 2002, 46: 2365-2372. 10.1128/AAC.46.8.2365-2372.2002PubMedCentralCrossRefPubMed
6.
Chou S: Cytomegalovirus UL97 mutations in the era of ganciclovir and maribavir. Rev Med Virol 2008, 18: 233-246. 10.1002/rmv.574CrossRefPubMed
7.
Wang LH, Peck RW, Yin Y, Allanson J, Wiggs R, Wire MB: Phase I safety and pharmacokinetic trials of 1263W94, a novel oral anti-human cytomegalovirus agent, in healthy and human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 2003, 47: 1334-1342. 10.1128/AAC.47.4.1334-1342.2003PubMedCentralCrossRefPubMed
8.
Michel D, Pavic I, Zimmermann A, Haupt E, Wunderlich K, Heuschmid M, Mertens T: The UL97 gene product of human cytomegalovirus is an early-late protein with a nuclear localization but is not a nucleoside kinase. J Virol 1996, 70: 6340-6346.PubMedCentralPubMed
9.
van Zeijl M, Fairhurst J, Baum EZ, Sun L, Jones TR: The human cytomegalovirus UL97 protein is phosphorylated and a component of virions. Virology 1997, 231: 72-80. 10.1006/viro.1997.8523CrossRefPubMed
10.
Prichard MN, Gao N, Jairath S, Mulamba G, Krosky P, Coen DM, Parker BO, Pari GS: A recombinant human cytomegalovirus with a large deletion in UL97 has a severe replication deficiency. J Virol 1999, 73: 5663-5670.PubMedCentralPubMed
11.
Baek MC, Krosky PM, He Z, Coen DM: Specific phosphorylation of exogenous protein and peptide substrates by the human cytomegalovirus UL97 protein kinase. Importance of the P+5 position. J Biol Chem 2002, 277: 29593-29599. 10.1074/jbc.M202312200CrossRefPubMed
12.
Kamil JP, Coen DM: Human cytomegalovirus protein kinase UL97 forms a complex with the tegument phosphoprotein pp65. J Virol 2007, 81: 10659-10668. 10.1128/JVI.00497-07PubMedCentralCrossRefPubMed
13.
Krosky PM, Baek MC, Jahng WJ, Barrera I, Harvey RJ, Biron KK, Coen DM, Sethna PB: The human cytomegalovirus UL44 protein is a substrate for the UL97 protein kinase. J Virol 2003, 77: 7720-7727. 10.1128/JVI.77.14.7720-7727.2003PubMedCentralCrossRefPubMed
14.
Baek MC, Krosky PM, Pearson A, Coen DM: Phosphorylation of the RNA polymerase II carboxyl-terminal domain in human cytomegalovirus-infected cells and in vitro by the viral UL97 protein kinase. Virology 2004, 324: 184-193. 10.1016/j.virol.2004.03.015CrossRefPubMed
15.
Kawaguchi Y, Matsumura T, Roizman B, Hirai K: Cellular elongation factor 1delta is modified in cells infected with representative alpha-, beta-, or gammaherpesviruses. J Virol 1999, 73: 4456-4460.PubMedCentralPubMed
16.
Marschall M, Marzi A, aus dem Siepen P, Jochmann R, Kalmer M, Auerochs S, Lischka P, Leis M, Stamminger T: Cellular p32 recruits cytomegalovirus kinase pUL97 to redistribute the nuclear lamina. J Biol Chem 2005, 280: 33357-33367. 10.1074/jbc.M502672200CrossRefPubMed
17.
Jault FM, Jault JM, Ruchti F, Fortunato EA, Clark C, Corbeil J, Richman DD, Spector DH: Cytomegalovirus infection induces high levels of cyclins, phosphorylated Rb, and p53, leading to cell cycle arrest. J Virol 1995, 69: 6697-6704.PubMedCentralPubMed
18.
Prichard MN, Sztul E, Daily SL, Perry AL, Frederick SL, Gill RB, Hartline CB, Streblow DN, Varnum SM, Smith RD, Kern ER: Human cytomegalovirus UL97 kinase activity is required for the hyperphosphorylation of retinoblastoma protein and inhibits the formation of nuclear aggresomes. J Virol 2008, 82: 5054-5067. 10.1128/JVI.02174-07PubMedCentralCrossRefPubMed
19.
Hume AJ, Finkel JS, Kamil JP, Coen DM, Culbertson MR, Kalejta RF: Phosphorylation of retinoblastoma protein by viral protein with cyclin-dependent kinase function. Science 2008, 320: 797-799. 10.1126/science.1152095CrossRefPubMed
20.
Felsani A, Mileo AM, Paggi MG: Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins. Oncogene 2006, 25: 5277-5285. 10.1038/sj.onc.1209621CrossRefPubMed
21.
Sun A, Bagella L, Tutton S, Romano G, Giordano A: From G0 to S phase: a view of the roles played by the retinoblastoma (Rb) family members in the Rb-E2F pathway. J Cell Biochem 2007, 102: 1400-1404. 10.1002/jcb.21609CrossRefPubMed
22.
Chou S, Wechel LC, Marousek GI: Cytomegalovirus UL97 kinase mutations that confer maribavir resistance. J Infect Dis 2007, 196: 91-94. 10.1086/518514CrossRefPubMed
23.
Williams SL, Hartline CB, Kushner NL, Harden EA, Bidanset DJ, Drach JC, Townsend LB, Underwood MR, Biron KK, Kern ER: In vitro activities of benzimidazole D- and L-ribonucleosides against herpesviruses. Antimicrob Agents Chemother 2003, 47: 2186-2192. 10.1128/AAC.47.7.2186-2192.2003PubMedCentralCrossRefPubMed
24.
Chou S, Van Wechel LC, Lichy HM, Marousek GI: Phenotyping of cytomegalovirus drug resistance mutations by using recombinant viruses incorporating a reporter gene. Antimicrob Agents Chemother 2005, 49: 2710-2715. 10.1128/AAC.49.7.2710-2715.2005PubMedCentralCrossRefPubMed
Metadata
Title
Conserved retinoblastoma protein-binding motif in human cytomegalovirus UL97 kinase minimally impacts viral replication but affects susceptibility to maribavir
Authors
Rachel B Gill
Samuel L Frederick
Caroll B Hartline
Sunwen Chou
Mark N Prichard
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Virology Journal / Issue 1/2009
Electronic ISSN: 1743-422X
DOI
https://doi.org/10.1186/1743-422X-6-9

Other articles of this Issue 1/2009

Virology Journal 1/2009 Go to the issue

Short report

Comparative analysis between a low pathogenic and a high pathogenic influenza H5 hemagglutinin in cell entry

Research

Molecular epidemiology of sexually transmitted human papillomavirus in a self referred group of women in Ireland

Research

From where did the 2009 'swine-origin' influenza A virus (H1N1) emerge?

Research

Proteomics computational analyses suggest that the bornavirus glycoprotein is a class III viral fusion protein (γ penetrene)

Research

Effective suppression of Dengue fever virus in mosquito cell cultures using retroviral transduction of hammerhead ribozymes targeting the viral genome

Research

Comparative analysis of Panicum streak virus and Maize streak virus diversity, recombination patterns and phylogeography
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits