A NOVEL, LOGICAL APPROACH TO HIV VACCINE DEVELOPMENT

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 目的：在体外诱导产生强的细胞毒性T淋巴细胞（CTL）反应， 缺乏其他免疫反应，使用几种不同的疫苗方法。 进展 迄今为止，所有艾滋病毒疫苗有效性试验都以失败告终。结构特点是各种 Env糖蛋白及其巨大的可变性使诱导 广泛反应的中和抗体。为了探索疫苗- 在缺乏中和抗体的情况下，诱导的细胞免疫应答可 控制复制的异源，粘膜病毒的挑战，在2007年，我们接种 8只猕猴，使用表达SIVmac 239的所有蛋白质的DNA/Ad 5方案 除了Env. 疫苗接种者产生针对11-34的高频T细胞应答 表位 2008年6月，我们开始用 异源生物分离物SIVsmE 660，使用旨在模拟典型的 人类艾滋病毒暴露导致感染。接种者的病毒载量为 在峰值（1.9 log减少，p 0.03）和设定点（3.3 log减少，p 0.03）时均显著降低 减少p0.003）。八分之六接种了疫苗 猕猴将急性峰值病毒复制控制在小于80，000 vRNA拷贝Eq/ml 在慢性期低于100 vRNA拷贝Eq/ml。接种疫苗的人数超过 感染后两年，病毒载量仍然低于检测水平。 接种者和对照者的死亡时间存在显著差异 感染后，由于SAIDS，虽然这个数据仍然是初步的。我们的结果 表明广泛的疫苗诱导的细胞免疫应答可以有效地 控制病原性异源艾滋病病毒的复制，这表明T细胞 的疫苗可能具有比以前认识到的更大的潜力。我们 在2010年发表了一篇论文，描述了免疫广度与 在Vif中的反应，以及在较小程度上的Gag，具有保护性。 这项研究使用WNPRC免疫学和病毒学服务（四聚体，流 流式细胞仪，Elispots）和WNPRC Genetics Services（MHC分型）。 出版物： Martins MA，Wilson NA，Reed JS，Ahn CD，Klimentidis YC，Allison DB，Watkins DI.异源猿后疫苗效力的T细胞相关性 免疫缺陷病毒的挑战。J Virol。2010年5月; 84（9）：4352-65。电子版2010年2月 17. PubMed PMID：20164222; PMID：20164222，PMCID：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.