Pathogenicity and immunogenicity of live attenuated SIV

减毒活SIV的致病性和免疫原性

• 批准号: 6559234
• 负责人: BARBARA K FELBER
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6559234
• 关键词: AIDS vaccines; Macaca mulatta; immunogenetics; live vaccine; microorganism immunology; nonhuman therapy evaluation; pathologic process; simian AIDSs; simian immunodeficiency virus; vaccine development; virulence; virus cytopathogenic effect; virus infection mechanism; virus replication

Live-attenuated SIV strains provide an important model to study cellular and viral determinants that contribute to disease development and they also provide a unique tool to study mechanisms leading to protective immunity. We focused our work on the viral Rev protein, a key regulatory factor, which is conserved among lentiviruses and is essential for promoting the export of the unspliced and intermediate-spliced mRNAs which encode the structural proteins. We postulated that a drastic change in the posttranscriptional regulation may affect the pathogenicity of HIV and SIV. To test this hypothesis, we found that the Rev-RRE regulation could be replaced by the posttranscriptional control mechanisms of the simian type D retroviruses. SRV expression is mediated via the cellular NXF1 (formerly called TAP) protein, which interacts with the viral RNA transport element CTE. Our demonstration that CTE could replace Rev/RRE in HIV and SIV resulting in production of infectious virus in PBMC opened the way for the evaluation of the pathogenicity of Rev-independent viruses in the presence of all other viral proteins using animal models. Studies from my lab have now demonstrated that changes of the posttranscriptional regulation of HIV and SIV profoundly alters the out-come of the infection. We have evidence from infection of neonatal, juvenile, and adult rhesus macaques that Rev-independent SIV strains lack pathogenicity (von Gegerfelt, A. S., et al. J Virol. 73:6159-6165, 1999; von Gegerfelt, A. S.et al. J Virol: in press 2001). Our data demonstrate that Rev/RRE regulatory mechanism is required for high levels of virus propagation and that this control mechanism plays an important role in the pathogenicity of SIV. The replacement of Rev/RRE by the NXF1/CTE system provides a novel approach to lower the virulence of a pathogenic lentivirus. The availability of non-pathogenic live-attenuated SIV strains provides us with a unique research tool to dissect pathogenic mechanisms leading to AIDS.

减毒SIV毒株为研究导致疾病发展的细胞和病毒决定因素提供了重要模型，它们也为研究导致保护性免疫的机制提供了独特的工具。我们的工作重点是病毒Rev蛋白，这是一个关键的调控因子，在慢病毒中是保守的，对于促进编码结构蛋白的非剪接和中间剪接mrna的输出是必不可少的。我们推测转录后调控的剧烈变化可能影响HIV和SIV的致病性。为了验证这一假设，我们发现Rev-RRE调控可以被猿猴D型逆转录病毒的转录后控制机制所取代。SRV的表达是通过细胞NXF1（以前称为TAP）蛋白介导的，该蛋白与病毒RNA转运元件CTE相互作用。我们证明CTE可以取代HIV和SIV中的Rev/RRE，从而在PBMC中产生感染性病毒，这为在所有其他病毒蛋白存在的情况下使用动物模型评估Rev-不依赖病毒的致病性开辟了道路。我实验室的研究现在已经证明，HIV和SIV转录后调控的变化深刻地改变了感染的结果。从新生、幼崽和成年恒河猴的感染中，我们有证据表明，不依赖于rev的SIV毒株缺乏致病性（von Gegerfelt, a.s.等）。中华微生物学杂志，2003；von Gegerfelt， A. s .等。J . Virol：出版社2001)。我们的数据表明，Rev/RRE调控机制是病毒高水平传播所必需的，这种调控机制在SIV的致病性中起着重要作用。用NXF1/CTE系统替代Rev/RRE提供了一种降低致病性慢病毒毒力的新方法。非致病性减毒SIV毒株的可用性为我们剖析导致艾滋病的致病机制提供了一种独特的研究工具。