A novel self-replicating chimeric lentivirus-like particle.
A novel self-replicating chimeric lentivirus-like particle.
复制标题
一种新型的自我复制嵌合慢病毒样颗粒。
DOI：
10.1128/jvi.05191-11
复制
发表时间：
2012
影响因子：
5.4
通讯作者：
Johnston,RobertE
中科院分区：
文献类型：
--
作者：
Jurgens,ChristyK;Young,KellyR;Madden,VictoriaJ;Johnson,PhilipR;Johnston,RobertE
成功的减毒活疫苗模拟自然暴露于病原体而不会引起疾病，并已成功地对抗了几种病毒。然而，安全方面的考虑阻碍了减毒人类免疫缺陷病毒(HIV)作为候选疫苗的发展。如果能够开发一种安全的、可复制的病毒疫苗，它可能有可能提供对艾滋病毒感染和疾病的重大保护。这里描述了一种新型的自我复制嵌合病毒候选疫苗的开发，该候选疫苗旨在提供对慢病毒样颗粒的自然暴露，并结合减毒活病毒疫苗的特性，而不存在与减毒慢病毒相关的固有安全问题。对甲型病毒委内瑞拉马脑炎病毒(VEE)基因组进行了修饰，使其表达编码结构蛋白Gag和Env的SHIV89.6P基因。从VEE RNA在灵长类细胞中表达的Gag和Env导致了在形态和功能上与慢病毒病毒粒子相似的颗粒的组装，并整合了甲型病毒RNA。慢病毒样嵌合颗粒感染CD4+细胞具有特异性和多产性，可导致RNA复制、Gag和Env的表达以及子代嵌合颗粒的产生。进一步的基因组修改旨在增强嵌合病毒基因组的包裹性，并表达用于颗粒成熟的减毒猴免疫缺陷病毒(SIV)蛋白酶，从而提高嵌合慢病毒样颗粒在细胞培养中的繁殖能力。这项研究为创建表达慢病毒结构蛋白并组装成感染性颗粒的嵌合病毒基因组的可行性提供了概念证明，以呈现其天然和功能构象的慢病毒免疫原。
Successful live attenuated vaccines mimic natural exposure to pathogens without causing disease and have been successful against several viruses. However, safety concerns prevent the development of attenuated human immunodeficiency virus (HIV) as a vaccine candidate. If a safe, replicating virus vaccine could be developed, it might have the potential to offer significant protection against HIV infection and disease. Described here is the development of a novel self-replicating chimeric virus vaccine candidate that is designed to provide natural exposure to a lentivirus-like particle and to incorporate the properties of a live attenuated virus vaccine without the inherent safety issues associated with attenuated lentiviruses. The genome from the alphavirus Venezuelan equine encephalitis virus (VEE) was modified to express SHIV89.6P genes encoding the structural proteins Gag and Env. Expression of Gag and Env from VEE RNA in primate cells led to the assembly of particles that morphologically and functionally resembled lentivirus virions and that incorporated alphavirus RNA. Infection of CD4+cells with chimeric lentivirus-like particles was specific and productive, resulting in RNA replication, expression of Gag and Env, and generation of progeny chimeric particles. Further genome modifications designed to enhance encapsidation of the chimeric virus genome and to express an attenuated simian immunodeficiency virus (SIV) protease for particle maturation improved the ability of chimeric lentivirus-like particles to propagate in cell culture. This study provides proof of concept for the feasibility of creating chimeric virus genomes that express lentivirus structural proteins and assemble into infectious particles for presentation of lentivirus immunogens in their native and functional conformation.