A NOVEL, LOGICAL APPROACH TO HIV VACCINE DEVELOPMENT

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：使用几种不同的疫苗方法，在没有其他免疫反应的情况下，产生强烈的细胞毒性T淋巴细胞(CTL)反应。 到目前为止，所有的艾滋病毒疫苗效力试验都以失败告终。包膜糖蛋白的结构特征及其巨大的变异性阻碍了诱导广泛反应的中和抗体的努力。为了探索在缺乏中和抗体的情况下，疫苗诱导的细胞免疫反应可以在多大程度上控制异源粘膜病毒的复制，2007年，我们用DNA/Ad5方案接种了8只猕猴，表达SIVmac239除Env外的所有蛋白。疫苗接种者针对11-34个表位进行高频T细胞反应。2008年6月，我们开始用异源生物分离物SIVsmE660挑战接种者和8只天然动物，使用一种旨在模拟导致感染的典型人类艾滋病毒暴露的方案。接种者的病毒载量在峰值(1.9个对数减少p0.03)和设定点(3.3个对数减少p<0.003)均显著低于对照组。在8只接种疫苗的猕猴中，有6只在慢性期将病毒复制的急性高峰控制在80000个vRNA拷贝Eq/ml以下，并控制在100vRNA拷贝Eq/ml以下。一些疫苗接种者在感染后1.5年以上，病毒载量仍低于检测水平。尽管这一数据仍是初步数据，但接种疫苗的人和对照组之间在SAID感染后死亡时间方面存在显著差异。我们的结果表明，广泛的疫苗诱导的细胞免疫反应可以有效地控制致病的、异种艾滋病病毒的复制，这表明基于T细胞的疫苗可能具有比以前所认识到的更大的潜力。我们有一份关于在这项研究中观察到的保护相关性的修订手稿。我们还有一份手稿正在准备中，描述了接种疫苗的动物和对照动物之间的长期结果差异。 本研究使用WNPRC免疫学和病毒学服务(四聚体、流式细胞仪、ELISPOTS)、WNPRC遗传学服务(MHC分型)。 出版物： 威尔逊·纳、Keele BF、Reed JS、Piaskowski SM、MacNair CE、Bett AJ、梁X、Wang F、Thoryk E、Heidecker GJ、Citron MP、黄L、林J、Vitelli S、Ahn CD、Kaizu M、Maness NJ、Reynolds MR、Friedrich TC、Loffredo JT、Rakasz EG、Erickson S、Allison DB、Piatak M Jr、Lifson JD、颤栗JW、Casimiro Dr、Shaw GM、Hahn BH、Watkins DI。疫苗诱导的细胞反应控制异种攻击后猴免疫缺陷病毒的复制。J·维罗尔。2009年7月；83(13)：6508-21。EPub 2009年4月29日PMID：19403685

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 generate strong cytotoxic T lymphocytes (CTL) responses, in the absence of other immune responses, using several different vaccine approaches. All HIV vaccine efficacy trials to date have ended in failure. Structural features of the Env glycoprotein and its enormous variability have frustrated efforts to induce broadly-reactive neutralizing antibodies. To explore the extent to which vaccine-induced cellular immune responses, in the absence of neutralizing antibodies, can control replication of a heterologous, mucosal viral challenge, in 2007, we vaccinated eight macaques with a DNA/Ad5 regimen expressing all of the proteins of SIVmac239 except Env. Vaccinees mounted high-frequency T cell responses against 11-34 epitopes. In June 2008, we began to challenge the vaccinees and eight na¿ve animals with the heterologous biological isolate SIVsmE660, using a regimen intended to mimic typical human HIV exposures resulting in infection. Viral loads in the vaccinees were significantly less at both peak (1.9 log reduction p0.03) and at set point (3.3 log reduction p0.003) than those of control na¿ve animals. Six of eight vaccinated macaques controlled acute peak viral replication to less than 80,000 vRNA copy Eq/ml and to less than 100 vRNA copy Eq/ml in the chronic phase. Some vaccinees are more than 1.5 years post infection and still have viral loads below levels of detection. Significant differences are present between vaccinees and controls for time of death post infection due to SAIDS, although this data is still preliminary. Our results demonstrate that broad vaccine-induced cellular immune responses can effectively control replication of a pathogenic, heterologous AIDS virus, suggesting that T cell based vaccines may have greater potential than previously appreciated. We have a manuscript in revision about correlates of protection observed during this study. We have an additional manuscript in preparation describing the long term outcome differences between the vaccinees and control animals. This research uses WNPRC Immunology and Virology Services (tetramers, flow cytometry instruments, Elispots), WNPRC Genetics Services (MHC typing). PUBLICATION: Wilson NA, Keele BF, Reed JS, Piaskowski SM, MacNair CE, Bett AJ, Liang X, Wang F, Thoryk E, Heidecker GJ, Citron MP, Huang L, Lin J, Vitelli S, Ahn CD, Kaizu M, Maness NJ, Reynolds MR, Friedrich TC, Loffredo JT, Rakasz EG, Erickson S, Allison DB, Piatak M Jr, Lifson JD, Shiver JW, Casimiro DR, Shaw GM, Hahn BH, Watkins DI. Vaccine-induced cellular responses control simian immunodeficiency virus replication after heterologous challenge. J Virol. 2009 Jul;83(13):6508-21. Epub 2009 Apr 29. PMID: 19403685