IMMUNOGENICITY AND PROTECTION OF LIVE ATTENUATED SIV239 DELTA NEF IN RHESUS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：利用SIV减毒活疫苗为研究有效的抗免疫缺陷病毒免疫应答提供一个独特的机会。 2006年，我们用SIV减毒株SIVmac239nef接种了10只恒河猴。我们使用各种检测方法监测了该队列中SIV特异性免疫反应的发展。2007年，接种疫苗的动物和幼稚的对照组一起接受了未克隆的SIVsmE660病毒的挑战。令人鼓舞的是，与单纯的对照组相比，接受SIVsmE660挑战的接种动物队列在挑战后长达4个月的时间里显著控制了病毒复制。特别令人感兴趣的是表达MHC I类分子MAMU-B*08和B*17的动物，它们几乎完全控制了急性病毒复制。这两个等位基因与控制急性病毒复制的相关性表明，CD8+T细胞是这种保护性免疫反应的主要介体。在攻击后11个月，4只接种疫苗的动物仍将SIVsmE660病毒复制控制在5000vRNA拷贝/毫升血浆以下。为了验证我们的假设，即CD8+细胞是这种低病毒复制的原因，我们在2008年使用了一种抗CD8抗体来清除外周血中的CD8+细胞。正如预期的那样，我们观察到在没有外周CD8+细胞的情况下病毒复制复发。在此期间，我们还想确定疫苗或挑战毒株是否在动物身上复制。我们惊讶地发现，只有疫苗株的病毒在四只暂时耗尽外周CD8+淋巴细胞的动物中的两只身上复制。在整个研究过程中的回顾分析证实，在测试的所有时间点，只有疫苗毒株在这两只动物身上检测到，这表明它们有可能实现对异源SIV挑战的灭菌免疫。此外，在感染慢性期失去病毒复制控制的接种动物中，我们检测到疫苗与挑战病毒株之间的重组。这些重组事件可能是导致动物未能遏制病毒复制的原因之一。这项研究使用并将继续使用WNPRC免疫遗传学和病毒学服务。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To use live-attenuated SIV vaccines as a unique opportunity to study effective anti-immunodeficiency virus immune responses. We vaccinated 10 rhesus macaques with the live-attenuated SIV strain SIVmac239nef in 2006. We monitored the development of SIV-specific immune responses in this cohort using a variety of assays. The vaccinated animals, along with naive controls, were challenged with the uncloned "swarm" virus SIVsmE660 in 2007. Encouragingly, the cohort of vaccinated animals challenged with SIVsmE660 significantly controlled virus replication in comparison to naive controls for up to 4 months post-challenge. Of particular interest were animals expressing the MHC class I molecules Mamu-B*08 and B*17 which had near complete control of acute virus replication. The association of these two alleles with control of acute virus replication suggests that CD8+ T cells are the primary mediators of this protective immune response. At 11 months post-challenge four vaccinated animals were still controlling SIVsmE660 virus replication below 5,000 vRNA copies/ml plasma. To test our hypothesis that CD8+ cells are responsible for this low virus replication we administered an anti-CD8 antibody to deplete CD8+ cells from the peripheral blood in 2008. As anticipated we observed a recrudescence in virus replication in the absence of peripheral CD8+ cells. During this time we also wanted to determine whether the vaccine or challenge strains of the virus was replicating in the animals. We were surprised to find that only the vaccine strain of the virus was replicating in two of the four animals temporarily depleted of their peripheral CD8+ lymphocytes. Retrospective analysis throughout the course of the study confirmed that only the vaccine strain of the virus was detectable in these two animals at all time points tested, suggesting it is possible that they were able to achieve sterilizing immunity against a heterologous SIV challenge. Additionally, in the vaccinated animals losing control of virus replication during the chronic phase of infection we detected recombination between the vaccine and challenge strains of the virus. These recombination events may have contributed to the animals failing to contain virus replication. The research used and will continue to use WNPRC Immunogenetics & Virology Services.