title: A spread-deficient cytomegalovirus for assessment of first-target cells in vaccination.
abstract: Human cytomegalovirus (HCMV) is a human pathogen that causes severe disease primarily in the immunocompromised or immunologically immature individual. To date, no vaccine is available. We describe use of a spread-deficient murine CMV (MCMV) as a novel approach for betaherpesvirus vaccination. To generate a spread-deficient MCMV, the conserved, essential gene M94 was deleted. Immunization with MCMV-DeltaM94 is apathogenic and protective against wild-type challenge even in highly susceptible IFNalphabetaR(-/-) mice. MCMV-DeltaM94 was able to induce a robust CD4(+) and CD8(+) T-cell response as well as a neutralizing antibody response comparable to that induced by wild-type infection. Endothelial cells were identified as activators of CD8(+) T cells in vivo. Thus, the vaccination with a spread-deficient betaherpesvirus is a safe and protective strategy and allows the linkage between cell tropism and immunogenicity. Furthermore, genomes of MCMV-DeltaM94 were present in lungs 12 months after infection, revealing first-target cells as sites of genome maintenance.
authors.affiliation: Max von Pettenkofer Institute, Ludwig Maximilians University, Pettenkoferstrasse 9a, Munich, Germany.
authors.forename: Christian Andreas
authors.initials: CA
authors.lastname: Mohr
authors.forename: Jurica
authors.initials: J
authors.lastname: Arapovic
authors.forename: Hermine
authors.initials: H
authors.lastname: Mühlbach
authors.forename: Marc
authors.initials: M
authors.lastname: Panzer
authors.forename: Annelies
authors.initials: A
authors.lastname: Weyn
authors.forename: Lars
authors.initials: L
authors.lastname: Dölken
authors.forename: Astrid
authors.initials: A
authors.lastname: Krmpotic
authors.forename: David
authors.initials: D
authors.lastname: Voehringer
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Ruzsics
authors.forename: Ulrich
authors.initials: U
authors.lastname: Koszinowski
authors.forename: Torsten
authors.initials: T
authors.lastname: Sacher
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D022482:Cytomegalovirus Vaccines / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D005260:Female; D017353:Gene Deletion; D016898:Interferon-alpha / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D016019:Survival Analysis; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D022482:Cytomegalovirus Vaccines; D016898:Interferon-alpha; D014613:Vaccines, Attenuated; D014764:Viral Proteins; D037521:Virulence Factors
references.citation: Genesis. 2001 May;30(1):36-44
references.pmid: 11353516
references.citation: J Pediatr. 1996 Mar;128(3):347-52
references.pmid: 8774502
references.citation: J Exp Med. 2004 Jan 5;199(1):131-6
references.pmid: 14699084
references.citation: Immunity. 2008 Sep 19;29(3):352-61
references.pmid: 18799143
references.citation: PLoS One. 2009;4(4):e5171
references.pmid: 19357779
references.citation: J Infect Dis. 2009 Jan 1;199(1):39-48
references.pmid: 19012492
references.citation: Immunol Cell Biol. 2007 Jan;85(1):46-54
references.pmid: 17146464
references.citation: J Immunol. 2007 Nov 1;179(9):6176-83
references.pmid: 17947693
references.citation: J Virol. 2005 Aug;79(15):9492-502
references.pmid: 16014912
references.citation: Nat Med. 2000 Oct;6(10):1183-6
references.pmid: 11017152
references.citation: J Virol. 1996 Jan;70(1):101-7
references.pmid: 8523513
references.citation: Immunol Cell Biol. 1998 Feb;76(1):34-40
references.pmid: 9553774
references.citation: J Virol. 2002 Apr;76(8):3615-25
references.pmid: 11907201
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14223-8
references.pmid: 14623981
references.citation: J Virol. 1992 Dec;66(12):7067-72
references.pmid: 1331509
references.citation: Immunity. 2008 Oct 17;29(4):650-9
references.pmid: 18957267
references.citation: Annu Rev Microbiol. 1987;41:543-71
references.pmid: 2825588
references.citation: J Virol. 2004 Mar;78(5):2255-64
references.pmid: 14963122
references.citation: J Virol. 2007 Dec;81(24):13825-34
references.pmid: 17913824
references.citation: Cell. 1994 Jan 14;76(1):17-27
references.pmid: 8287475
references.citation: Cell Host Microbe. 2008 Apr 17;3(4):263-72
references.pmid: 18407069
references.citation: J Infect Dis. 1995 Jan;171(1):26-32
references.pmid: 7798679
references.citation: Clin Infect Dis. 2008 Sep 1;47(5):702-11
references.pmid: 18652557
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14759-63
references.pmid: 9405686
references.citation: J Gen Virol. 2005 Sep;86(Pt 9):2401-2410
references.pmid: 16099897
references.citation: Ann Emerg Med. 2009 Jun;53(6):792-5
references.pmid: 19028409
references.citation: J Biol Chem. 1999 Jan 1;274(1):305-15
references.pmid: 9867845
references.citation: N Engl J Med. 2001 May 3;344(18):1366-71
references.pmid: 11333993
references.citation: Vaccine. 2003 Jun 2;21(19-20):2632-42
references.pmid: 12744900
references.citation: J Infect Dis. 2003 Mar 15;187(6):988-99
references.pmid: 12660946
references.citation: J Virol. 1990 Mar;64(3):1079-85
references.pmid: 2154594
references.citation: Clin Infect Dis. 2004 Jul 15;39(2):155-61
references.pmid: 15307021
references.citation: Immunity. 2002 Nov;17(5):653-64
references.pmid: 12433371
references.citation: J Virol. 2003 Oct;77(20):11274-8
references.pmid: 14512575
references.citation: Exp Mol Pathol. 2007 Jun;82(3):269-79
references.pmid: 17320076
references.citation: Virology. 2006 Sep 15;353(1):210-9
references.pmid: 16797052
references.citation: N Engl J Med. 1992 Mar 5;326(10):663-7
references.pmid: 1310525
references.citation: J Virol. 1996 Jun;70(6):3339-45
references.pmid: 8648663
references.citation: J Infect Dis. 1985 Dec;152(6):1192-6
references.pmid: 2999256
references.citation: JAMA. 2003 Feb 26;289(8):1008-11
references.pmid: 12597753
references.citation: Arch Virol. 2000;145(12):2601-18
references.pmid: 11205107
references.citation: PLoS One. 2010 Mar 12;5(3):e9681
references.pmid: 20300633
references.citation: J Virol. 1993 Sep;67(9):5360-6
references.pmid: 8394453
references.citation: Virology. 2006 Jan 5;344(1):230-9
references.pmid: 16364753
references.citation: J Exp Med. 1998 Aug 3;188(3):577-88
references.pmid: 9687534
references.citation: J Exp Med. 1994 May 1;179(5):1713-7
references.pmid: 8163949
references.citation: J Virol. 2004 Sep;78(18):10023-33
references.pmid: 15331735
references.citation: J Clin Microbiol. 1998 Oct;36(10):2893-9
references.pmid: 9738040
references.citation: Nat Immunol. 2001 Nov;2(11):1077-84
references.pmid: 11668340
references.citation: J Virol. 2009 Sep;83(17):8869-84
references.pmid: 19535440
references.citation: J Virol. 1994 Oct;68(10):6243-53
references.pmid: 8083964
references.citation: Gastroenterology. 2010 Jan;138(1):336-46
references.pmid: 19737567
references.citation: J Virol. 1996 Jan;70(1):78-83
references.pmid: 8523595
references.citation: Nat Rev Immunol. 2002 Nov;2(11):831-44
references.pmid: 12415307
references.citation: Science. 1994 Jun 24;264(5167):1918-21
references.pmid: 8009221
references.citation: J Infect Dis. 1997 Jan;175(1):179-84
references.pmid: 8985216
references.citation: J Virol. 1996 Dec;70(12):8833-49
references.pmid: 8971012
references.citation: Dev Biol Stand. 1982;52:287-304
references.pmid: 6299836
references.citation: J Infect Dis. 1989 May;159(5):860-5
references.pmid: 2540247
references.citation: Expert Opin Biol Ther. 2001 May;1(3):401-12
references.pmid: 11727514
references.citation: Virology. 2001 Sep 30;288(2):256-63
references.pmid: 11601897
references.citation: J Virol. 2009 Sep;83(18):9611-5
references.pmid: 19553308
references.citation: J Virol. 2004 Oct;78(20):11187-97
references.pmid: 15452238
references.citation: N Engl J Med. 2005 Sep 29;353(13):1350-62
references.pmid: 16192480
references.citation: J Virol. 1987 Oct;61(10):3102-8
references.pmid: 3041033
references.citation: J Gen Virol. 2009 Jan;90(Pt 1):33-43
references.pmid: 19088270
references.citation: N Engl J Med. 1986 May 29;314(22):1414-8
references.pmid: 3010113
references.citation: J Exp Med. 2008 Aug 4;205(8):1819-28
references.pmid: 18606858
references.citation: J Exp Med. 1989 Apr 1;169(4):1199-212
references.pmid: 2564415
references.citation: J Virol. 2006 Jan;80(1):73-84
references.pmid: 16352532
references.citation: J Antimicrob Chemother. 2000 Apr;45 Suppl T3:35-43
references.pmid: 10855770
references.citation: Virus Genes. 2002;24(1):39-48
references.pmid: 11928987
references.citation: Comp Immunol Microbiol Infect Dis. 1991;14(2):97-105
references.pmid: 1657515
references.citation: J Med Virol. 2000 Oct;62(2):127-39
references.pmid: 11002240
references.citation: J Virol. 1992 Jan;66(1):341-8
references.pmid: 1309250