Analysis of host immune responses involved in control of HIV infections

在HIV感染的自然过程中，细胞毒性T淋巴细胞（CTL）应答在原发感染的消退中发挥核心作用，但不能控制病毒复制，导致建立持续的HIV感染。我们一直在研究疫苗诱导的CTL应答对猴免疫缺陷病毒（SIV）复制的影响，以阐明HIV持续感染的机制。我们已经发现一组恒河猴共享主要组织相容性复合体单倍型90-120-a，显示基于疫苗的SIV控制。他们中的一些人在病毒控制1年后再次出现血浆病毒血症，并伴有Gag CTL逃逸突变的积累。在本研究中，我们研究了具有这些多个CTL逃逸突变的SIV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，突变的SIV具有从三个表位特异性CTL逃逸的Gag突变，并且在体外显示出降低的复制能力。这表明病毒通过以病毒适应度为代价逃离CTL而再次出现，表明这三种表位特异性CTL应答参与了病毒控制。仅在急性AIDS模型中的一个临床前AIDS疫苗试验中报道了病毒利用来自显性CTL的单一逃逸突变逃避免疫控制（Nature 415：335，2002）。本报告还没有明确多个表位特异性CTL是否可以参与免疫缺陷病毒复制的疫苗控制，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。

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.