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Early localized SIV-specific CD8 T cells response to pathogenic SIV is correlated with successful SIV vaccine.

机译：早期定位的SIV特异性CD8 T细胞对致病性SIV的反应与成功的SIV疫苗相关。

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摘要

Live-attenuated lentivirus vaccines are the most effective in inducing protection against subsequent challenge with pathogenic lentiviruses. For example, infection with live-attenuated simian immunodeficiency viruses (SIVs) including nonpathogenic simian-human immunodeficiency virus (SHIV) 89.6, and SIVDeltanef in macaques provides protection against subsequent challenge with highly pathogenic strains of SIV. The mechanism by which live-attenuated SIVs induce protection is not well understood. My central hypothesis is that an early SIV-specific CD8 T cell response in lymph nodes and at the site of infection is responsible for the protection induced from live-attenuated SIV vaccines. The rationale for this hypothesis stems from our previous studies showing that SIV disseminates throughout the body by one week post-infection but SIV-specific CD8 T cell responses are too late and not detected in situ until the second and third weeks post-infection. For the present study, rhesus macaques were immunized intravenously with live non-pathogenic SHIV89.6, or SIVDeltanef and then challenged intravaginally with pathogenic SIVmac239, or SIVmac251. Using the experimental approach of in situ tetramer staining combined with immunohistochemistry, confocal microscopy and quantitative image analyses, I determined: (1) localization and quantification of virus-specific CD8 T cells (2) phenotypic changes in lytic granule contents of virus-specific CD8+ T cells and (3) virus-specific CD8 T cells interacting with CD83 + cells in tissues from these animals. My main results show that an early but not necessarily robust SIV-specific CD8 T cell response localized to lymph nodes and genital tissues correlated with protection in these animals. In addition, the majority of SIV-specific CD8 T cells that I observed in vaccinated animals showed little to no perforin expression, compared to cells from non-vaccinated and pathogenic SIV-infected animals. Lastly, I also observed an increase in the interaction of vaccine-induced SIV-specific T cells with CD83+ dendritic cells after pathogenic SIV challenge in immunized animals. These results indicate that vaccine-induced protection correlates with early localized SIV-specific CD8 T cells that show little to no perforin expression at the portal of viral entry and lymph nodes. Additionally my studies indicate that vaccine-induced protection correlates with increased interactions of SIV-specific CD8 T cells with mature dendritic cells. These studies provide a better understanding of immune correlates involved in the protection afforded by live-attenuated SIV vaccines, and provide insights into what is needed to create a successful HIV vaccine.
机译：减毒活慢病毒疫苗最有效地诱导针对随后的病原性慢病毒攻击的保护作用。例如，用猕猴中的减毒的猿猴免疫缺陷病毒（SIV）感染，包括非致病性猿猴-人类免疫缺陷病毒（SHIV）89.6和SIVDeltanef，可以保护其免受高致病性SIV株随后的攻击。减毒活的SIV诱导保护的机制尚不清楚。我的中心假设是，淋巴结和感染部位的早期SIV特异性CD8 T细胞应答是由减毒活SIV疫苗诱导的保护作用的原因。该假设的基本原理来自于我们先前的研究，表明SIV在感染后一周内在全身传播，但是SIV特异性CD8 T细胞反应太迟了，直到感染后第二和第三周才被原位检测到。对于本研究，恒河猴猕猴用活的非致病性SHIV89.6或SIVDeltanef进行了静脉免疫，然后用病原性SIVmac239或SIVmac251进行了阴道内攻击。使用原位四聚体染色与免疫组织化学，共聚焦显微镜和定量图像分析相结合的实验方法，我确定：（1）病毒特异性CD8 T细胞的定位和定量（2）病毒特异性CD8 +的裂解颗粒含量的表型变化T细胞和（3）病毒特异性CD8 T细胞与这些动物组织中的CD83 +细胞相互作用。我的主要结果表明，早期但不一定强大的SIV特异性CD8 T细胞应答定位于淋巴结和生殖器组织，与这些动物的保护相关。另外，与未接种和致病性SIV感染的动物的细胞相比，我在接种过的动物中观察到的大多数SIV特异性CD8 T细胞几乎没有穿孔素表达。最后，我还观察到在致病性SIV攻击后，免疫动物中疫苗诱导的SIV特异性T细胞与CD83 +树突状细胞的相互作用增加。这些结果表明，疫苗诱导的保护作用与早期定位的SIV特异性CD8 T细胞有关，后者在病毒进入和淋巴结的入口几乎没有穿孔素表达。另外，我的研究表明，疫苗诱导的保护作用与SIV特异性CD8 T细胞与成熟树突状细胞相互作用的增强有关。这些研究提供了对减毒活SIV疫苗提供的保护所涉及的免疫相关性的更好理解，并提供了对成功制作HIV疫苗所需要的见解。

著录项

  • 作者

    Hong, Jung Joo.;

  • 作者单位

    University of Minnesota.;

  • 授予单位 University of Minnesota.;
  • 学科 Biology Virology.Biology Veterinary Science.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 141 p.
  • 总页数 141
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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