T Cell Functionality and Control of Acute HIV Infection

描述（由申请方提供）：大量证据表明，CD 8+细胞在控制HIV/SIV疾病进展中发挥关键作用，但使用标准方法（MHC I类四聚体和单功能分析）测量的HIV特异性CD 8 + T细胞应答的数量和广度均与复制或疾病进展的控制无关。最近，使用一种新的多功能分析方法，我们已经确定了CD 8 + T细胞功能的模式，似乎提供歧视艾滋病毒疾病进展状态。在慢性不受控制的感染期间，HIV感染的受试者具有功能有限的HIV特异性CD 8 + T细胞应答，而长期非进展者保持多功能应答。我们相信，这些多功能模式可以使我们能够确定自然免疫保护的相关性，而且，它们可能对疫苗开发策略产生影响。定义急性感染期间的HIV特异性CD 8 + T细胞应答是相关的，因为这一期间的事件定义了未来的疾病进展。此外，有效的艾滋病毒疫苗需要在感染的这一特定阶段激发保护性反应。我们的目标是定义HIV特异性CD 8 + T细胞的多功能和表型特征，这些细胞在原发性感染过程中出现，确定它们是如何被调节的，并定义它们与病毒控制和疾病进程的关系。我们还将确定这些反应是否可以通过接种疫苗来改变，使用DNA/腺病毒方法作为模型，并利用少数接种疫苗的HIV感染者的独特资源。总之，这些研究将提供有关免疫保护相关性的关键信息，可以测量HIV候选疫苗的潜在保护作用。开发针对HIV的疫苗需要了解感染发生后针对HIV的自然免疫反应。在这项提案中，我们将确定免疫系统如何在早期感染期间对抗艾滋病毒，并将这些知识应用于艾滋病毒疫苗的开发和测试。

DESCRIPTION (provided by applicant): Considerable evidence indicates that CD8+ cells play a critical role in controlling HIV/SIV disease progression, but neither the quantity nor breadth of the HIV-specific CD8+ T cell response as measured using standard approaches (MHC class I tetramer and single function analysis) conclusively correlate with control of replication or disease progression. Recently, using a novel polyfunctional analytical approach, we have identified patterns of CD8+ T cell function that appear to provide discriminate HIV disease progression status. HIV-infected subjects during chronic uncontrolled infection possess functionally limited HIV-specific CD8+ T cell responses, whereas long-term nonprogressors maintain polyfunctional responses. We believe that these polyfunctional patterns may enable us to identify correlates of natural immune protection and, furthermore, that they may have implications for vaccine development strategies. It is pertinent to define HIV-specific CD8+ T cell responses during acute infection, as the events during this period define future disease progression. Furthermore, an effective HIV vaccine will need to stimulate responses protective during this particular phase of infection. Our goals are to define the polyfunctional and phenotypic characteristics of HIV-specific CD8+ T cells that arise during primary infection, determine how they are modulated, and define their relationship to viral control and disease course. We will also determine if these responses can be altered by vaccination, using as a model a DNA/Adenovirus approach and exploiting the unique resource of a small number of vaccinated individuals who became HIV infected. Together, these studies will provide critical information regarding immune correlates of protection against which HIV vaccine candidates can be measured for potential protective effects. Lay Description: Development of a vaccine against HIV requires the understanding of the natural immune responses against HIV after infection occurs. In this proposal, we will determine how the immune system fights HIV during early infection and apply this knowledge to the development and testing of HIV vaccines.