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首页> 外文OA文献 >Functional Human Immunodeficiency Virus Type 1 (HIV-1) Gag-Pol or HIV-1 Gag-Pol and Env Expressed from a Single Rhabdovirus-Based Vaccine Vector Genome
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Functional Human Immunodeficiency Virus Type 1 (HIV-1) Gag-Pol or HIV-1 Gag-Pol and Env Expressed from a Single Rhabdovirus-Based Vaccine Vector Genome

机译：从基于单个弹状病毒的疫苗载体基因组表达的功能性人类免疫缺陷病毒1型（HIV-1）Gag-Pol或HIV-1 Gag-Pol和Env

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Recombinant rabies virus (RV) vaccine strain-based vectors have been successfully developed as vaccines against other viral diseases (J. P. McGettigan et al., J. Virol. 75:4430-4434, 2001; McGettigan et al., J. Virol. 75:8724-8732, 2001; C. A. Siler et al., Virology 292:24-34, 2002), and safety concerns have recently been addressed (McGettigan et al., J. Virol. 77:237-244, 2003). However, size limitations of the vectors may restrict their use for development of vaccine applications that require the expression of large and multiple foreign antigens. Here we describe a new RV-based vaccine vehicle expressing 4.4 kb of the human immunodeficiency virus type 1 (HIV-1) Gag-Pol precursor Pr160. Our results indicate that Pr160 is expressed and processed, as demonstrated by immunostaining and Western blotting. Electron microscopy studies showed both immature and mature HIV-1 virus-like particles (VLPs), indicating that the expressed HIV-1 Gag Pr55 precursor was processed properly by the HIV-1 protease. A functional assay also confirmed the cleavage and functional expression of the HIV-1 reverse transcriptase (RT) from the modified RV genome. In the next step, we constructed and recovered a new RV vaccine strain-based vector expressing a chimeric HIV-189.6P RV envelope protein from an additional RV transcription unit located between the RV nucleoprotein (N) and phosphoprotein (P) in addition to HIV-1 Pr160. The 2.2-kb chimeric HIV-1/RV envelope protein is composed of the HIV-1 Env ectodomain (ED) and transmembrane domain (TD) fused to RV glycoprotein (G) cytoplasmic domain (CD), which is required for efficient incorporation of HIV-1 Env into RV particles. Of note, the expression of both HIV-1 Env and HIV-1 Pr160 resulted in an increase in the rhabdoviral genome of >55%. Both rhabdovirus-expressed HIV-1 precursor proteins were functional, as indicated by RT activity and Env-based fusion assays. These findings demonstrate that both multiple and very large foreign genes can be effectively expressed by RV-based vectors. This research opens up the possibility for the further improvement of rhabdovirus-based HIV-1 vaccines and their use to express large foreign proteins, perhaps from multiple human pathogens.
机译：基于重组狂犬病毒（RV）疫苗株的载体已成功开发为针对其他病毒性疾病的疫苗（JP McGettigan等，J。Virol。75：4430-4434，2001； McGettigan等，J。Virol。75 ，例如，J.Virol。：8724-8732，2001； CA Siler等，Virology 292：24-34，2002），并且最近已经解决了安全问题（McGettigan等，J.Virol.77：237-244，2003）。但是，载体的大小限制可能会限制其在需要表达大量和多种外源抗原的疫苗开发中的应用。在这里，我们描述了一种新的基于RV的疫苗载体，该疫苗载体表达4.4 kb的人类1型免疫缺陷病毒（HIV-1）Gag-Pol前体Pr160。我们的结果表明，如免疫染色和蛋白质印迹所示，Pr160被表达和加工。电子显微镜研究显示未成熟和成熟的HIV-1病毒样颗粒（VLP），表明表达的HIV-1 Gag Pr55前体已被HIV-1蛋白酶正确处理。功能测定还证实了来自修饰的RV基因组的HIV-1逆转录酶（RT）的切割和功能表达。在下一步中，我们从HIV之外的RV核蛋白（N）和磷蛋白（P）之间的另一个RV转录单元中，构建并回收了新的基于RV疫苗株的载体，该载体表达嵌合的HIV-189.6P RV包膜蛋白-1 Pr160。 2.2 kb的嵌合HIV-1 / RV包膜蛋白由与RV糖蛋白（G）胞质域（CD）融合的HIV-1 Env胞外域（ED）和跨膜域（TD）组成，这是有效掺入的HIV-1 Env变成RV颗粒。值得注意的是，HIV-1 Env和HIV-1 Pr160的表达导致弹状病毒基因组的增加> 55％。 RT活动和基于Env的融合测定均表明，两种弹状病毒表达的HIV-1前体蛋白均具有功能。这些发现表明，基于RV的载体可以有效地表达多个和非常大的外源基因。这项研究为进一步改进基于弹状病毒的HIV-1疫苗以及将其用于表达可能来自多种人类病原体的大型外源蛋白提供了可能性。

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