title: Inactivation of the viral interleukin 1beta receptor improves CD8+ T-cell memory responses elicited upon immunization with modified vaccinia virus Ankara.
abstract: Interleukin 1 (IL1) is an important regulator of inflammatory responses and contributes to host immune defence against infection. Vaccinia virus encodes a viral soluble IL1beta receptor (IL1betaR), which modulates the acute-phase host response to infection and might influence the induction of immune responses against virus-associated antigens. Here, modified vaccinia virus Ankara (MVA) mutants defective in IL1betaR production were produced by insertion of selectable marker gene sequences that precisely deleted the IL1betaR coding sequences from the MVA genome (MVA-DeltaIL1betaR). Analysis of MVA mutants indicated that deletion of the IL1betaR gene did not abrogate the formation of MVA progeny upon tissue culture propagation. After high-dose intranasal infection with MVA-DeltaIL1betaR, mice showed no signs of fever or other illness, suggesting that the avirulent phenotype remained preserved for MVA-DeltaIL1betaR. Following vaccination of mice, MVA-DeltaIL1betaR or non-mutated MVA induced similar acute-phase immune responses. Importantly, when monitored at the memory phase, significantly higher vaccinia virus-specific total CD8(+) and HLA-A*0201-binding peptide epitope-specific T-cell responses were found after vaccination of HLA-A*0201-transgenic and non-transgenic mice with MVA-DeltaIL1betaR. Moreover, 4-6 months after vaccination, MVA-DeltaIL1betaR provided higher levels of protection against lethal respiratory challenge infection with virulent vaccinia virus strain Western Reserve compared with wild-type MVA. These data suggest that deletion of the viral IL1betaR gene may be considered a relevant approach to amplify the virus-specific CD8+ memory T-cell response and duration of protective immunity obtained after MVA vaccination.
authors.affiliation: GSF Institute of Molecular Virology and Institute of Virology, Technical University of Munich, Trogerstrasse 4b, 81675 München, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Staib
authors.affiliation: GSF Institute of Molecular Virology and Institute of Virology, Technical University of Munich, Trogerstrasse 4b, 81675 München, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Kisling
authors.affiliation: GSF Institute of Molecular Virology and Institute of Virology, Technical University of Munich, Trogerstrasse 4b, 81675 München, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Erfle
authors.affiliation: Department of Virology, Paul-Ehrlich-Institute, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Germany.|GSF Institute of Molecular Virology and Institute of Virology, Technical University of Munich, Trogerstrasse 4b, 81675 München, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Sutter
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D017353:Gene Deletion; D007114:Immunization; D007156:Immunologic Memory / Q000276:immunology*; D007375:Interleukin-1 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics* / Q000378:metabolism; D014615:Vaccinia / Q000276:immunology / Q000517:prevention & control; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D007375:Interleukin-1; D018123:Receptors, Interleukin; D011991:Receptors, Virus; D014765:Viral Vaccines