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)反应在原发感染中发挥核心作用，但未能控制病毒复制，导致HIV持续感染。我们一直在研究疫苗诱导的CTL反应对猕猴免疫缺陷病毒(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一个主要组织相容性复合体单倍型90-120-a，这表明基于疫苗的SIV控制。他们中的一些人在病毒控制一年后表现出血浆病毒血症的复发，并积累了Gag CTL逃逸突变。在这项研究中，我们检测了SIV与这些多个CTL逃逸突变的复制能力，突变体SIV具有从三个表位特异性CTL逃逸的Gag突变，并且与野生型SIV和感染早期快速选择的单一CTL逃逸突变的SIV相比，其体外复制能力减弱。这表明病毒是通过以病毒适合性代价逃离CTL而重新出现的，这表明这三种表位特异性CTL反应参与了病毒控制。在急性艾滋病模型中，只有一次临床前艾滋病疫苗试验报告了通过显性CTL的单一逃逸突变来逃避免疫控制的病毒(自然，415：335,2002)。这份报告没有明确多个表位特异性CTL是否参与了基于疫苗的免疫缺陷病毒复制控制，但我们的结果表明，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.