Staib Caroline, Kisling Sigrid, Erfle Volker, Sutter Gerd
GSF Institute of Molecular Virology and Institute of Virology, Technical University of Munich, Trogerstrasse 4b, 81675 München, Germany.
Department of Virology, Paul-Ehrlich-Institute, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Germany.
J Gen Virol. 2005 Jul;86(Pt 7):1997-2006. doi: 10.1099/vir.0.80646-0.
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-A0201-binding peptide epitope-specific T-cell responses were found after vaccination of HLA-A0201-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.
白细胞介素1（IL1）是炎症反应的重要调节因子，有助于宿主对感染的免疫防御。痘苗病毒编码一种病毒可溶性IL1β受体（IL1βR），它可调节宿主对感染的急性期反应，并可能影响针对病毒相关抗原的免疫反应的诱导。在此，通过插入可选择标记基因序列产生了在IL1βR产生方面有缺陷的改良安卡拉痘苗病毒（MVA）突变体，该序列精确地从MVA基因组中删除了IL1βR编码序列（MVA-ΔIL1βR）。对MVA突变体的分析表明，IL1βR基因的缺失并不影响MVA在组织培养繁殖时子代的形成。用MVA-ΔIL1βR进行高剂量鼻内感染后，小鼠没有出现发热或其他疾病迹象，这表明MVA-ΔIL1βR仍保持无毒表型。给小鼠接种疫苗后，MVA-ΔIL1βR或未突变的MVA诱导了相似的急性期免疫反应。重要的是，在记忆期进行监测时，在用MVA-ΔIL1βR接种HLA-A0201转基因和非转基因小鼠后，发现痘苗病毒特异性总CD8(+)和HLA-A0201结合肽表位特异性T细胞反应显著更高。此外，接种疫苗4 - 6个月后，与野生型MVA相比，MVA-ΔIL1βR对致死性呼吸道强毒痘苗病毒株Western Reserve攻击感染提供了更高水平的保护。这些数据表明，删除病毒IL1βR基因可能被认为是一种相关方法，可用于增强MVA疫苗接种后获得的病毒特异性CD8+记忆T细胞反应和保护性免疫的持续时间。
