A NOVEL, LOGICAL APPROACH TO HIV VACCINE DEVELOPMENT

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 目的：在小鼠体内产生强烈的细胞毒性T淋巴细胞(CTL)反应。 使用几种不同的疫苗方法，没有其他免疫反应。 进展 到目前为止，所有的艾滋病毒疫苗效力试验都以失败告终。的结构特点。 包膜糖蛋白及其巨大的变异性阻碍了诱导 广谱反应性中和抗体。为了探索疫苗在多大程度上- 诱导的细胞免疫反应，在没有中和抗体的情况下，可以 控制复制的异源、粘膜病毒的挑战，2007年，我们接种了疫苗 用DNA/Ad5方案表达SIVmac239全部蛋白的8只猕猴 除Env.疫苗接种者对11-34疫苗产生高频T细胞反应 表位。 2008年6月，我们开始挑战疫苗接种者和8只幼年动物 异源生物分离物SIVsmE660，使用一种旨在模仿典型 人类接触艾滋病毒会导致感染。接种者体内的病毒载量是 峰值(1.9个对数减少p0.03)和设定点(3.3个对数)均显著减少 降低p0.003)。八个人中有六个接种了疫苗 猕猴将病毒复制的急性高峰控制在8万vRNA拷贝Eq/ml以下 慢性期低于100vRNA拷贝数Eq/ml。接种疫苗的人不止是 感染两年后，病毒载量仍低于检测水平。 接种疫苗的人和对照组之间的死亡时间存在显著差异。 由于SAID感染后，尽管这一数据仍是初步数据。我们的结果 证明广泛的疫苗诱导的细胞免疫反应可以有效地 控制一种致病的、异种艾滋病病毒的复制，表明T细胞 以疫苗为基础的疫苗可能比以前认识到的更有潜力。我们 2010年发表的一篇论文描述了免疫广度之间的相关性 在VIF中的反应，在较小的程度上，是保护性的GAG。 这项研究使用了WNPRC免疫学和病毒学服务(四聚体，Flow 细胞仪，Elispots)和WNPRC遗传学服务(MHC分型)。 出版物： 马丁斯·马，威尔逊·纳，里德·JS，安·CD，Klimentidis YC，艾莉森·DB，沃特金斯 迪。异种猿猴接种后T细胞与疫苗效力的相关性 免疫缺陷病毒挑战。J·维罗尔。2010年5月；84(9)：4352-65。EPub 2010年2月 17.PubMed PMID：20164222；PMID：20164222，PMC2863752。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To generate strong cytotoxic T lymphocytes (CTL) responses, in the absence of other immune responses, using several different vaccine approaches. PROGRESS 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. Vaccinees are more than two 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 published a paper in 2010 describing a correlation between the breadth of immune responses in Vif and, to a lesser extent, Gag that are protective. This research uses WNPRC Immunology and Virology Services (tetramers, flow cytometry instruments, Elispots) and WNPRC Genetics Services (MHC typing). PUBLICATION: Martins MA, Wilson NA, Reed JS, Ahn CD, Klimentidis YC, Allison DB, Watkins DI. T-cell correlates of vaccine efficacy after a heterologous simian immunodeficiency virus challenge. J Virol. 2010 May; 84(9):4352-65. Epub 2010 Feb 17. PubMed PMID: 20164222; PMID: 20164222, PMCID: PMC2863752.