Lentiviral vectors encoding HIV-1 polyepitopes induce broad CTL responses in vivo
Lentiviral vectors encoding HIV-1 polyepitopes induce broad CTL responses in vivo
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DOI：
10.1038/sj.mt.6300135
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发表时间：
2007-06-01
影响因子：
12.4
通讯作者：
Charneau, Pierre
中科院分区：
文献类型：
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作者：
Iglesias, Maria Candela;Mollier, Karine;Charneau, Pierre
慢病毒载体已经在抗肿瘤和抗病毒模型中作为疫苗接种载体进行了测试。它们有效地刺激树突状细胞并刺激针对编码抗原的强烈T细胞应答。然而，其刺激针对几种抗原的细胞毒性T淋巴细胞（CTL）应答的能力尚未被评估。广泛的抗人类免疫缺陷病毒1（HIV-1）T细胞免疫应答对于控制HIV复制是重要的。我们评估了编码多表位的慢病毒载体诱导广泛的抗HIV CTL应答的潜力。我们构建了两个慢病毒载体编码HLA-A2或HLA-B7限制性多表位，并通过直接注射载体颗粒在HLA-A2或HLA-B7转基因小鼠中评估其免疫原性。体外细胞毒性试验表明，一个单一的免疫诱导一个强大的，多样化的，和持久的CTL反应在两种小鼠模型。CTL应答针对HLA-A2系统中的所有13个表位和HLA-B7系统中的12个表位中的8个。第二次免疫增加了HLA-A2系统中的应答小鼠的数量，但在HLA-B7系统中没有。HLA-B7免疫的小鼠在体内对大多数表位和裂解的负载肽的靶细胞产生强烈的干扰素-γ（IFN-γ）分泌T细胞应答。HLA-B7小鼠的CTL应答仅部分依赖于CD 4 T细胞的帮助。这项工作强调了慢病毒载体作为获得性免疫缺陷综合征治疗性疫苗候选者的潜力。
Lentiviral vectors have been tested as vaccination vectors in anti-tumoral and anti-viral models. They efficiently transduce dendritic cells and stimulate strong T-cell responses against the encoded antigen. However, their capacity to stimulate a cytotoxic T-lymphocyte (CTL) response against several antigens has not been evaluated. Broad anti-human immunodeficiency virus 1 (HIV-1) T-cell immune responses are important for the control of HIV replication. We evaluated the potential of polyepitope-encoding lentiviral vectors to induce broad anti-HIV CTL responses. We constructed two lentiviral vectors coding for an HLA-A2- or HLA-B7-restricted polyepitope and evaluated their immunogenicity by direct injection of vector particles in HLA-A2 or HLA-B7 transgenic mice. In vitro cytotoxicity assays showed that a single immunization induces a strong, diversified, and long-lasting CTL response in both mouse models. CTL responses were directed against all 13 epitopes in the HLA-A2 system and 8 out of 12 in the HLA-B7 system. A second immunization augmented the number of responding mice in the HLA-A2 system but not in the HLA-B7 system. HLA-B7-immunized mice mounted strong interferon-gamma (IFN-gamma)-secreting T-cell responses against a majority of the epitopes and lysed peptide-loaded target cells in vivo. CTL responses in HLA-B7 mice were only partially dependent on CD4 T-cell help. This work underlines the potential of lentiviral vectors as candidates for therapeutic vaccination against acquired immunodeficiency syndrome.