Carolina Vaccine Institute, Research Triangle Park, North Carolina, USA.
J Virol. 2012 Jan;86(1):246-61. doi: 10.1128/JVI.05191-11. Epub 2011 Oct 19.
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.
成功的减毒活疫苗模拟了病原体的自然暴露，而不会引起疾病，并已成功对抗几种病毒。然而，安全问题阻止了减毒人类免疫缺陷病毒 (HIV) 作为疫苗候选物的开发。如果能够开发出安全的、复制的病毒疫苗，它可能有潜力提供针对 HIV 感染和疾病的显著保护。本文描述了一种新型自复制嵌合病毒疫苗候选物的开发，该候选物旨在提供对类似于慢病毒的颗粒的自然暴露，并结合减毒活病毒疫苗的特性，而没有与减毒慢病毒相关的固有安全问题。来自甲病毒委内瑞拉马脑炎病毒 (VEE) 的基因组被修饰以表达 SHIV89.6P 基因，该基因编码结构蛋白 Gag 和 Env。在灵长类细胞中，从 VEE RNA 表达 Gag 和 Env 导致组装的颗粒在形态和功能上类似于慢病毒病毒颗粒，并掺入甲病毒 RNA。嵌合类慢病毒样颗粒感染 CD4+细胞是特异性和有生产力的，导致 RNA 复制、Gag 和 Env 的表达以及产生嵌合颗粒的后代。旨在增强嵌合病毒基因组的包装并表达减毒猴免疫缺陷病毒 (SIV) 蛋白酶以进行颗粒成熟的进一步基因组修饰提高了嵌合类慢病毒样颗粒在细胞培养中繁殖的能力。本研究为创建表达慢病毒结构蛋白并组装成感染性颗粒以呈现慢病毒免疫原的嵌合病毒基因组的可行性提供了概念证明，这些免疫原以其天然和功能构象呈现。
