1887

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 IL1 receptor (IL1R), 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 IL1R production were produced by insertion of selectable marker gene sequences that precisely deleted the IL1R coding sequences from the MVA genome (MVA-ΔIL1R). Analysis of MVA mutants indicated that deletion of the IL1R gene did not abrogate the formation of MVA progeny upon tissue culture propagation. After high-dose intranasal infection with MVA-ΔIL1R, mice showed no signs of fever or other illness, suggesting that the avirulent phenotype remained preserved for MVA-ΔIL1R. Following vaccination of mice, MVA-ΔIL1R 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-ΔIL1R. Moreover, 4–6 months after vaccination, MVA-ΔIL1R 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 IL1R 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.

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2005-07-01
2020-01-19
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