Bongard Nadine, Lapuente Dennis, Windmann Sonja, Dittmer Ulf, Tenbusch Matthias, Bayer Wibke
Institute for Virology, University Hospital Essen, University Duisburg-Essen, Virchowstr. 179, 45147, Essen, Germany.
Department of Molecular and Medical Virology, Institute of Hygiene and Microbiology, Ruhr-University Bochum, Bochum, Germany.
Retrovirology. 2017 Apr 27;14(1):28. doi: 10.1186/s12977-017-0352-7.
Retroviral envelope (Env) proteins are known to exhibit immunosuppressive properties, which become apparent not only in retroviral infections, but also in gene-based immunizations using retroviral immunogens, where envelope interferes with the induction of CD8 T cell responses towards another, simultaneously or subsequently delivered, immunogen.
In the Friend retrovirus mouse model, immunization with a plasmid encoding the Friend murine leukemia virus (F-MuLV) Leader-Gag protein resulted in induction of a strong GagL-specific CD8 T cell response, while the response was completely abrogated by co-immunization with an F-MuLV Env-encoding plasmid. In order to overcome this interference of retroviral envelope, we employed plasmids encoding the cytokines interleukin (IL) 1β, IL2, IL12, IL15, IL21, IL28A or granulocyte-macrophage colony-stimulating factor (GM-CSF) as genetic adjuvants. Co-application of plasmids encoding IL2, IL12, IL21, IL28A and especially GM-CSF rescued the induction of GagL-specific CD8 T cells in mice vaccinated with FV Leader-Gag and Env. Mice that were immunized with plasmids encoding Leader-Gag and Env and the cytokines IL1β, IL12, IL15, IL28A or GM-CSF, but not Leader-Gag and Env without any cytokine, showed significantly reduced viral loads upon a high-dose Friend virus challenge infection.
Our data demonstrate the potency of cytokine-encoding vectors as adjuvants and immune modulators in composite vaccines for anti-retroviral immunization.
逆转录病毒包膜（Env）蛋白具有免疫抑制特性，这不仅在逆转录病毒感染中明显，在使用逆转录病毒免疫原的基因免疫中也很明显，其中包膜会干扰针对另一种同时或随后递送的免疫原的CD8 T细胞反应的诱导。
在Friend逆转录病毒小鼠模型中，用编码Friend鼠白血病病毒（F-MuLV）前导-Gag蛋白的质粒免疫可诱导强烈的GagL特异性CD8 T细胞反应，而与编码F-MuLV Env的质粒共同免疫则完全消除了该反应。为了克服逆转录病毒包膜的这种干扰，我们使用编码细胞因子白细胞介素（IL）1β、IL2、IL12、IL15、IL21、IL28A或粒细胞-巨噬细胞集落刺激因子（GM-CSF）的质粒作为基因佐剂。共同应用编码IL2、IL12、IL21、IL28A尤其是GM-CSF的质粒可挽救在用FV前导-Gag和Env疫苗接种的小鼠中GagL特异性CD8 T细胞的诱导。用编码前导-Gag和Env以及细胞因子IL1β、IL12、IL15、IL28A或GM-CSF的质粒免疫的小鼠，但不是用没有任何细胞因子的前导-Gag和Env免疫的小鼠，在高剂量Friend病毒攻击感染后病毒载量显著降低。
我们的数据证明了编码细胞因子的载体作为抗逆转录病毒免疫复合疫苗中的佐剂和免疫调节剂的效力。
