T-bet and the Th1/Th17 balance in Acute HIV infection

急性 HIV 感染中的 T-bet 和 Th1/Th17 平衡

• 批准号: 8134863
• 负责人: LAURIE Hollis GLIMCHER
• 金额: $ 23.98万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134863
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Acute Disease; Adoptive Transfer; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Count; Cells; Complementary DNA; Data; Development; Equilibrium; Frequencies; Gastrointestinal tract structure; Generations; Genes; Genetic Programming; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; Highly Active Antiretroviral Therapy; Human; Immune response; Immunity; Infection; Inflammation; Inflammatory; Interleukin-17; Interleukin-2; Intestines; Laboratories; Macrophage Activation; Microbe; Modeling; Murine Acquired Immunodeficiency Syndrome; Mus; Patients; Phenotype; Population; Production; Regulatory T-Lymphocyte; Retroviridae; Role; Surface; T-Lymphocyte; T-bet protein; Testing; Th1 Cells; Transcription Coactivator; Viral; Viral Load result; Viremia; base; cytokine; in vivo; insight; mouse model; overexpression; pathogen; public health relevance; research study; response; transcription factor

DESCRIPTION (provided by applicant): Acute HIV infection is accompanied by inflammation and by a profound loss of CD4+ T cells from the gastrointestinal (GI) tract. Systemic inflammation arising from the gut is now thought to be pathogenic in progression of HIV/AIDS. We hypothesize that a shift towards a Th17 response and away from a pro-inflammatory Th1 response in the setting of acute infection will be protective. We have discovered that the transcription factor T-bet controls the Th1/Th17 balance in vivo both as an activator of Th1 differentiation and as a repressor of Th17 differentiation. Hence, in contrast to the protective role of T-bet for most pathogens, T-bet may actually be deleterious for a patient acutely infected with HIV because it enhances a pro-inflammatory Th1 response in the gut. Of note, there are additional reasons to believe that silencing T-bet will be protective in the setting of acute HIV infection. First, T-bet is a repressor of IL-2 in CD4+ and CD8+ T cells, a cytokine which has been shown to correlate with lower viral load in the elite controller population. Second, T-bet-/- CD4 cells are polyfunctional i.e. "multiple cytokine-secreting", a phenotype recently associated with viral control. We suggest that reducing T-bet expression will 1) increase gut protective Th17 cells; 2) reduce pro-inflammatory Th1-driven responses such as macrophage activation; 3) increase IL-2 production necessary for functional CD8+ cell T responses and 4) increase numbers of polyfunctional T cells. We will use two different mouse models of AIDS to establish the function of T-bet in vivo. The MAIDs model has provided valuable insights into the immune response against retroviruses and will allow us to test the effect of T-bet absence and T-bet overexpression easily. However, its resemblance to human HIV/AIDs is only partial. If our proof-of-principle experiments in the MAIDS model are encouraging, we will move quickly to the more relevant model, a humanized mouse model called BLT, to ask whether 1) T-bet silencing in human cells provides protection against HIV in vivo and 2) T-bet overexpression exacerbates acute HIV infection. Guided by our results in the MAIDS model, human HSCs will be transduced with lentiviral T-bet siRNAs and T-bet cDNAs for adoptive transfer experiments to BLT mice. Hence, the goal of this proposal is to further explore the function and mechanism of action of a transcriptional activator/repressor, isolated in our laboratory, in the immune response to HIV. It is based on strong preliminary data that T-bet controls the development and function of Th1 cells and represses the development of IL-17 and IL-2 producing cells. The emphasis will be on the role of this gene and its products in the setting of acute HIV infection and ultimately in the generation of durable protective immunity to HIV. PUBLIC HEALTH RELEVANCE: Systemic inflammation arising from the gut is now thought to be pathogenic in progression of acute HIV/AIDS. We have discovered that the transcription factor T-bet controls the Th1/Th17 balance in vivo both as an activator of Th1 differentiation and as a repressor of Th17 differentiation- hence, in contrast to the protective role of T-bet for most pathogens, T-bet may actually be deleterious for a patient infected with HIV because it enhances a pro-inflammatory Th1 response in the gut. We will test the hypothesis that blocking T-bet expression will 1) increase gut protective Th17 cells 2) reduce pro-inflammatory Th1-driven responses 3) increase IL-2 production necessary for functional CD8+ cell T responses 4) increase numbers of polyfunctional T cells and 5) will ameliorate acute disease in two different mouse models of AIDS: MAIDS and the BLT humanized mouse model.

描述（由申请人提供）：急性 HIV 感染伴有炎症和胃肠道 (GI) 中 CD4+ T 细胞的严重损失。现在认为，肠道引起的全身炎症是艾滋病毒/艾滋病进展的致病因素。我们假设在急性感染情况下转向 Th17 反应并远离促炎 Th1 反应将具有保护作用。我们发现转录因子 T-bet 在体内控制 Th1/Th17 平衡，既作为 Th1 分化的激活剂，又作为 Th17 分化的阻抑剂。因此，与 T-bet 对大多数病原体的保护作用相反，T-bet 实际上可能对急性感染 HIV 的患者有害，因为它增强了肠道中的促炎 Th1 反应。值得注意的是，还有其他理由相信沉默 T-bet 在急性 HIV 感染的情况下具有保护作用。首先，T-bet 是 CD4+ 和 CD8+ T 细胞中 IL-2 的抑制因子，IL-2 是一种细胞因子，已被证明与精英控制人群中较低的病毒载量相关。其次，T-bet-/- CD4 细胞具有多功能性，即“分泌多种细胞因子”，这是最近与病毒控制相关的一种表型。我们建议减少 T-bet 表达将 1) 增加肠道保护性 Th17 细胞； 2) 减少促炎性Th1驱动的反应，例如巨噬细胞活化； 3) 增加功能性 CD8+ 细胞 T 反应所需的 IL-2 产量，4) 增加多功能 T 细胞的数量。我们将使用两种不同的艾滋病小鼠模型来建立 T-bet 的体内功能。 MAIDs 模型为针对逆转录病毒的免疫反应提供了宝贵的见解，并使我们能够轻松测试 T-bet 缺失和 T-bet 过度表达的影响。然而，它与人类艾滋病毒/艾滋病的相似之处只是部分的。如果我们在 MAIDS 模型中进行的原理验证实验令人鼓舞，我们将迅速转向更相关的模型，即一种名为 BLT 的人源化小鼠模型，以探究 1) 人类细胞中的 T-bet 沉默是否可以在体内提供针对 HIV 的保护，以及 2) T-bet 过度表达是否会加剧急性 HIV 感染。根据我们在 MAIDS 模型中的结果，人类 HSC 将用慢病毒 T-bet siRNA 和 T-bet cDNA 转导，用于 BLT 小鼠的过继转移实验。因此，本提案的目标是进一步探索我们实验室分离的转录激活剂/阻遏物在 HIV 免疫反应中的功能和作用机制。基于强有力的初步数据，T-bet 控制 Th1 细胞的发育和功能，并抑制 IL-17 和 IL-2 产生细胞的发育。重点将放在该基因及其产物在急性艾滋病毒感染中以及最终在产生针对艾滋病毒的持久保护性免疫力中的作用。 公共卫生相关性：现在认为，肠道引起的全身炎症是急性艾滋病毒/艾滋病进展的致病因素。我们发现，转录因子 T-bet 在体内控制着 Th1/Th17 平衡，既作为 Th1 分化的激活剂，又作为 Th17 分化的阻遏物，因此，与 T-bet 对大多数病原体的保护作用相反，T-bet 实际上可能对感染 HIV 的患者有害，因为它增强了肠道中的促炎 Th1 反应。我们将测试以下假设：阻断 T-bet 表达将 1) 增加肠道保护性 Th17 细胞 2) 减少促炎性 Th1 驱动的反应 3) 增加功能性 CD8+ 细胞 T 反应所需的 IL-2 产生 4) 增加多功能 T 细胞的数量，5) 将改善两种不同的 AIDS 小鼠模型（MAIDS 和 BLT 人源化小鼠模型）的急性疾病。