Optimization of Human Immunodeficiency Virus Gag Expression by Newcastle Disease Virus Vectors for the Induction of Potent Immune Responses
Optimization of Human Immunodeficiency Virus Gag Expression by Newcastle Disease Virus Vectors for the Induction of Potent Immune Responses
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DOI：
10.1128/jvi.01443-08
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发表时间：
2009-01-15
影响因子：
5.4
通讯作者：
Garcia-Sastre, Adolfo
中科院分区：
文献类型：
--
作者：
Carnero, Elena;Li, Wenjing;Garcia-Sastre, Adolfo
开发人类免疫缺陷病毒（HIV）疫苗的一个有吸引力的策略是使用具有已证实的安全性特征并且在人类中不存在预先存在的免疫力的病毒载体，例如纽卡斯尔病病毒（NDV）。已经产生了几种NDV疫苗载体，并且已经用不同的动物模型研究了它们的免疫原性。然而，尚未进行系统的研究来评估外源抗原进入NDV的最佳插入位点，从而导致对抗原特异性的增强的免疫应答。在这篇文章中，我们描述了表达HIV Gag的NDV在小鼠中产生Gag特异性免疫应答的能力。我们还通过产生重组NDV-HIVGag病毒确定了NDV基因组中的最佳插入位点，其中HIV gag位于整个NDV病毒基因组的不同转录位置。所有重组病毒都是活的，在含胚鸡蛋中生长至相似滴度，并以稳定的方式表达Gag。我们的体内实验表明，更高的HIV Gag蛋白表达与增强的CD 8（+）T细胞介导的免疫应答和针对表达HIV Gag的牛痘病毒攻击的保护性免疫正相关。我们还在P和M基因之间的所述最佳位置插入了HIV gag的密码子优化版本。表达密码子优化版本的HIV gag的病毒诱导了小鼠中蛋白质的更高表达和针对HIV Gag的增强的免疫应答。这些结果表明，针对增加NDV抗原表达的策略导致增强的免疫原性和疫苗效力。
One attractive strategy for the development of a human immunodeficiency virus (HIV) vaccine is the use of viral vectors with a proven safety profile and an absence of preexisting immunity in humans, such as Newcastle disease virus (NDV). Several NDV vaccine vectors have been generated, and their immunogenicities have been investigated with different animal models. However, a systematic study to evaluate the optimal insertion site of the foreign antigens into NDV that results in enhanced immune responses specific to the antigen has not yet been conducted. In this article, we describe the ability of NDV expressing HIV Gag to generate a Gag-specific immune response in mice. We also have determined the optimal insertion site into the NDV genome by generating recombinant NDV-HIVGag viruses in which HIV gag was located at different transcriptional positions throughout the NDV viral genome. All recombinant viruses were viable, grew to similar titers in embryonated chicken eggs, and expressed Gag in a stable manner. Our in vivo experiments revealed that higher HIV Gag protein expression positively correlates with an enhanced CD8(+) T-cell-mediated immune response and protective immunity against challenge with vaccinia virus expressing HIV Gag. We also inserted a codon-optimized version of HIV gag in the described best location, between the P and M genes. Virus expressing the codon-optimized version of HIV gag induced a higher expression of the protein and an enhanced immune response against HIV Gag in mice. These results indicate that strategies directed toward increasing antigen expression by NDV result in enhanced immunogenicity and vaccine efficacy.