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Analysis of host immune responses involved in control of HIV infections

分析参与控制 HIV 感染的宿主免疫反应

基本信息

批准号：
16017221
负责人：
MATANO Tetsuro
金额：
$ 9.6万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

In the natural courses of HIV infections, cytotoxic T lymphocyte (CTL) responses play a central role in resolution from primary infection but fail to control viral replication leading to establishment of persistent HIV infection. We have been examining the effect of vaccine-induced CTL responses on simian immunodeficiency virus (SIV) replication in macaques to elucidate the mechanism for persistent HIV infection. We have found a group of rhesus macaques sharing a major histocompatibility complex haplotype 90-120-a that show vaccine-based SIV control. Some of them have shown reappearance of plasma viremia after 1-year of viral control with accumulation of Gag CTL escape mutations. In this study, we have examined the replicative ability of SIV with these multiple CTL escape mutations.The mutant SIV had Gag mutations escaping from three epitope-specific CTLs and showed diminished replicative ability in vitro compared to the wild-type SIV and the SW with a single CTL escape mutation rapidly-selected in the early phase of infection. This indicates that the viruses reappeared by escaping from CTLs with viral fitness costs, suggesting involvement of these three epitope-specific CTL responses in viral control. Viral evasion from immune control with a single escape mutation from a dominant CTL has been reported only in one preclinical AIDS vaccine trial in an acute AIDS model (Nature 415 : 335, 2002). This report has not made it clear whether multiple epitope-specific CTLs can be involved in the vaccine-based control of immunodeficiency virus replication, but our results indicate that accumulation of multiple CTL escape mutations can result in viral breakthrough from the vaccine-based control of SIV replication.

在HIV感染的自然过程中，细胞毒性T淋巴细胞（CTL）反应在原发性感染的解决中起着核心作用，但不能控制病毒复制，从而导致持久性HIV感染的建立。我们一直在研究疫苗诱导的CTL反应对猴免疫缺陷病毒（SIV）在猕猴体内复制的影响，以阐明持续HIV感染的机制。我们发现一组恒河猴具有主要的组织相容性复合体90-120-a单倍型，显示基于疫苗的SIV控制。其中一些人在经过1年的病毒控制后，随着Gag CTL逃逸突变的积累，血浆病毒血症再次出现。在这项研究中，我们检测了SIV与这些多重CTL逃逸突变的复制能力。与野生型SIV和在感染早期快速选择的具有单个CTL逃逸突变的SW相比，突变型SIV具有从三个表位特异性CTL逃逸的Gag突变，并且在体外显示出较低的复制能力。这表明病毒以病毒适应度为代价从CTL中逃脱而重新出现，表明这三种表位特异性CTL反应参与了病毒控制。仅在一个急性艾滋病模型的临床前艾滋病疫苗试验中报道了病毒通过显性CTL的单一逃逸突变逃避免疫控制（Nature 415: 335, 2002）。这篇报道并没有明确多个表位特异性CTL是否可以参与基于疫苗的免疫缺陷病毒复制控制，但我们的研究结果表明，多个CTL逃逸突变的积累可以导致病毒突破基于疫苗的SIV复制控制。