Mechanisms of SIV suppression by CD8+ lymphocytes

CD8淋巴细胞抑制SIV的机制

• 批准号: 8492022
• 负责人: Guido Silvestri
• 金额: $ 73.32万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-25 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492022
• 关键词: AIDS Vaccines; AIDS vaccine development; Adenoviruses; Affect; Anatomy; Animals; Antigens; Antiviral Agents; Apoptosis; Binding; Blood; CCR5 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chronic; Clinical Trials; Complex; Cytotoxic T-Lymphocytes; Development; Epitopes; Frequencies; Gene Expression; HIV; HIV-1; Human; Infection; Interferons; Interleukin-15; Interleukin-7; Knowledge; Location; Longevity; Lymphocyte Depletion; Macaca mulatta; Measures; Mediating; Memory; Organ; Pattern; Phase; Plasma; Predisposition; Production; Rest; Role; SIV; Series; T-Lymphocyte; TNF gene; Tissues; Virion; Virus; Virus Replication; Work; antiretroviral therapy; base; cell killing; chemokine; cytokine; design; env Gene Products; in vivo; insight; killings; macrophage; mathematical model; neutralizing antibody; pathogen; protective effect; research study

DESCRIPTION (provided by applicant): Several observations indicate that CD8+ T cells are important in controlling virus replication during chronic HIV and SIV infection. Paramount among these observations is that experimental in vivo depletion of CD8+ lymphocytes in SIV-infected rhesus macaques (RM) is followed by a dramatic increase in virus replication. However, the mechanisms by which CD8+ T cells mediate this antiviral effect are still poorly understood, as emphasized by the negative result of the Merck Adenovirus-based, cytotoxic T lymphocyte (CTL)-inducing candidate AIDS vaccine in a large phase IIb clinical trial. In a recent study (Klatt et al., PLoS Pathogens, in press), we sought to assess the mechanisms underlying the antiviral effect of CD8+ lymphocytes during chronic SIVmac239 infection of RMs by treating two groups of animals (i.e., CD8+ lymphocyte-depleted or controls) with antiretroviral therapy (ART). Using a well-accepted mathematical model to calculate the in vivo lifespan of productively infected cells, we found that, in both early and late SIV infection, depletion of CD8+ lymphocytes did not change the in vivo lifespan of infected cells. This result indicates that SIV suppression mediated by CD8+ lymphocytes goes above and beyond the direct killing of cells producing virus, and suggests that more studies are needed to fully understand the antiviral role of CD8+ T cells during SIV infection. Here we propose to conduct a series of experiments of in vivo CD8+ lymphocyte depletion aimed at better elucidating the antiviral effects of these cells during chronic SIV mac239 infection of RMs. In the first Aim, we will determine how CD8+ lymphocytes impact the average lifespan of in vivo infected cells in Mamu-B*08/17+ RMs that show better control of virus replication upon SIV mac239 infection. In the second Aim, we will determine how CD8+ lymphocyte depletion induces changes in the fraction, type, and location of SIV infected cells as well as the burst size of virus production. In the third Aim, we will assess how CD8+ lymphocyte depletion affects the production of soluble antiviral factors (i.e., cytokines and chemokine) and alters the intrinsic susceptibility of CD4+ T cells to SIV infection by changing their level of activation, proliferation, CCR5 expression, and intracellular levels of host restriction factors. We believe that these experiments will provide important insights into CD8+ lymphocyte inhibition of virus replication during SIV infection. Ultimately, we hope that this knowledge will favor the rational design of an effective CTL-based AIDS vaccine. Our current inability to design immunogens that induce broadly reactive neutralizing antibodies against the HIV-1 Envelope protein has shifted the focus of the AIDS vaccine development effort to the design of immunogens that induce high levels of HIV-specific CD8+ T cells. The experiments included in this proposal are aimed at elucidating the mechanisms by which CD8+ lymphocytes suppress virus replication in SIV-infected RMs. The results generated here will provide correlates of CD8+ lymphocyte-mediated protection to be used to rank and prioritize the development of candidate AIDS vaccines for use in humans.

描述（由申请人提供）： 几个观察结果表明，CD8+ T细胞对于控制慢性HIV和SIV感染期间的病毒复制很重要。这些观察结果中最重要的是，在SIV感染的恒河猕猴（RM）中，CD8+淋巴细胞的实验性体内耗竭之后，病毒复制急剧增加。然而，CD8+ T细胞介导该抗病毒作用的机制仍然很少了解，这是由于基于Merck腺病毒的基于默克病毒的细胞毒性T淋巴细胞（CTL）诱导候选候选疫苗的负面结果所强调的。在最近的一项研究（Klatt等人，PLOS病原体，印刷中），我们试图评估CD8+淋巴细胞在慢性SIVMAC239感染RMS期间CD8+淋巴细胞在RMS期间的抗病毒效应的基础机制（即CD8+淋巴细胞增多或对照组）用替代术（即用Antirets）进行治疗。使用良好认可的数学模型来计算有效感染细胞的体内寿命，我们发现，在SIV早期和晚期感染中，CD8+淋巴细胞的耗竭都没有改变感染细胞的体内寿命。该结果表明，由CD8+淋巴细胞介导的SIV抑制超过了产生病毒细胞的直接杀死，并表明需要更多的研究以充分了解SIV感染过程中CD8+ T细胞的抗病毒作用。在这里，我们建议进行一系列体内CD8+淋巴细胞耗竭，以更好地阐明RMS的慢性SIV MAC239感染过程中这些细胞的抗病毒作用。在第一个目标中，我们将确定CD8+淋巴细胞如何影响MAMU-B*08/17+ RMS体内感染细胞的平均寿命，这些寿命可以更好地控制SIV MAC239感染后对病毒复制的控制。在第二个目标中，我们将确定CD8+淋巴细胞耗竭如何诱导SIV感染细胞的分数，类型和位置以及病毒产生的爆发尺寸的变化。在第三个目标中，我们将评估CD8+淋巴细胞的耗竭如何影响可溶性抗病毒因子的产生（即细胞因子和趋化因子），并改变CD4+ T细胞对SIV对SIV感染的内在敏感性，通过改变其激活，增殖，CCR5表达和内部固定限制因子的水平来改变其SIV感染。我们认为，这些实验将为SIV感染期间病毒复制的CD8+淋巴细胞抑制提供重要见解。最终，我们希望这些知识将有利于有效的基于CTL的艾滋病疫苗的合理设计。我们目前无法设计针对HIV-1包膜蛋白的广泛反应性中和抗体的免疫原子，已将AIDS疫苗发育努力的重点转移到诱导高水平HIV HIV特异性CD8+ T细胞的免疫原子上。该提案中包括的实验旨在阐明CD8+淋巴细胞抑制SIV感染RMS病毒复制的机制。此处生成的结果将提供CD8+淋巴细胞介导的保护的相关性，用于对候选AIDS疫苗的开发进行排序和优先级，以用于人类。