HIV-Induced CD4 T-Cell Depletion: An Innate Host Defense Gone Awry?

HIV 诱导的 CD4 T 细胞耗竭：先天宿主防御出了问题？

• 批准号: 8500196
• 负责人: Warner C. Greene
• 金额: $ 17.64万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500196
• 关键词: AIM2 gene; Acquired Immunodeficiency Syndrome; Antiviral Agents; Antiviral Therapy; Apoptosis; Attenuated; Binding; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Caspase-1; Cell Death; Cells; Cessation of life; Complex; Cytoplasm; DNA; Dementia; Disease; Disease Progression; Drug resistance; Event; Exhibits; FDA approved; Family; Frequencies; Genes; Genetic; Genetic Transcription; Glyburide; HIV; HIV Infections; HIV-1; Host Defense; Human; Immune response; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferon Activation; Interferons; Interleukin-1; Lead; Life Cycle Stages; Link; Lymphoid; Lymphoid Tissue; Malignant Neoplasms; Mediating; Memory; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Opportunistic Infections; Oral; Paper; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Play; Process; Production; Progressive Disease; Protein Family; Recruitment Activity; Regimen; Relative (related person); Research; Rest; Reverse Transcription; Role; Series; Spleen; Sulfonylurea Compounds; T-Cell Depletion; Testing; Tissues; Tonsil; Toxic effect; Transcript; Viral; Virus; Virus Diseases; base; caspase-3; cytokine; helicase; in vivo; inhibitor/antagonist; insight; killings; macrophage; member; novel strategies; novel therapeutic intervention; pathogen; prevent; receptor; response; secretion process; sensor; success; viral DNA

DESCRIPTION (provided by applicant): Progressive depletion of CD4 T cells is a halmark of untreated acquired immune deficiency syndrome (AIDS), yet the mechanism by which CD4 T cells die during HIV infection remains poorly understood. HIV can directly infect and kill CD4 T cels however too few productively infected cells are present in vivo to explain the masive CD4 T-cell losses that occur. Using primary human lymphoid aggregate cultures (HLAC) formed with tonsil or spleen tissue, we have explored how CD4 T cells die during HIV infection in lymphoid tissues. Our studies have revealed several surprises including: (1) Quiescent "bystander" CD4 T cells, which are not permissive to productive infection by X4-tropic HIV-1, die in huge numbers as a result of abortive viral infection accompanied by the the accumulation of incomplete viral DNA transcripts in the cytoplasm; (2) Death is not cause by a toxic effect of these DNA or other viral products; rather the CD4 T cells die as a result of a powerful innate immune response launched against the viral DNA, resulting in the production of interferon-¿ and activation of caspase-3 and caspase-1; (3) Ultimately, this response leads to inflammasome assembly and caspase-1 activation triggering the release of bioactive IL-1¿ and induction of pyroptosis, an intensely inflammatory form of programmed cell death. These events can establish a vicious cycle, whereby dying CD4 T cells release inflammatory mediators that attract additional cells for new rounds of abortive infection and death; 4) Surprisingly, HIV-mediated CD4 T cell depletion by pyroptosis can be completely blocked by specific class of FDA-approved oral sulfonylurea drugs currently used to treat type II diabetes. We now propose a set of pivotal new studies. In Specific Aim 1, we will test whether this mechanism of CD4 T cell depletion also extends to CCR5-expressing CD4 T cells that often display a higher state of cellular activation and thus might be less susceptible to abortive infection. In Specific Aim 2, we propose to identify the cytoplasmic sensor(s) that detects the viral DNA. Multiple sensors may activate the interferon response and the activation of caspase-1 within inflammasomes. In Specific Aim 3, we propose to identify the inflammasome that recruits caspase-1 to process and release IL-1¿ and to induce pyroptosis. Together, these studies will yield new insights into the mechanism(s) underlying HIV- induced depletion of CD4 T cells-the fundamental problem in AIDS. This new understanding could lead to an entirely new therapeutic approach to AIDS involving interdiction of the host innate immune response that promotes both CD4 T cell death and inflammation. This approach could form a strong adjunct to traditional antiviral therapy and might be particularly beneficial for patients exhibiting broad drug resistance or rapid progression of disease.

描述(由申请人提供)：CD4T细胞的进行性耗竭是未经治疗的获得性免疫缺陷综合征(AIDS)的标志，然而，CD4T细胞在HIV感染过程中死亡的机制仍然知之甚少。HIV可以直接感染和杀死CD4T细胞，然而体内存在的生产性感染细胞太少，无法解释发生的主要CD4T细胞损失。利用扁桃体或脾组织形成的原代人类淋巴聚集培养(HLAC)，我们探索了淋巴组织中CD4T细胞在HIV感染过程中如何死亡。我们的研究揭示了几个令人惊讶的现象，包括：(1)静止的“旁观者”CD4T细胞，它们不允许被X4嗜性HIV-1生产性感染，由于流产的病毒感染伴随细胞质中不完全的病毒DNA转录本的积累，导致大量死亡；(2)死亡不是由这些DNA或其他病毒产物的毒性作用引起的；相反，CD4T细胞死亡是由于针对病毒DNA发起的强大的先天免疫反应，导致产生干扰素并激活caspase-3和caspase-1；(3)最终，这种反应导致炎性小体组装和caspase-1激活，触发生物活性IL-1的释放，并诱导肾下垂，这是一种强烈的炎症性形式的程序性细胞死亡。这些事件可能会建立一个恶性循环，死亡的CD4T细胞释放炎症介质，吸引更多的细胞进行新一轮的流产感染和死亡；4)令人惊讶的是，由HIV介导的由下垂引起的CD4T细胞耗尽可以被FDA批准的目前用于治疗II型糖尿病的特定类型的口服磺脲类药物完全阻断。我们现在提出一套关键的新研究。在特定的目标1中，我们将测试这种CD4T细胞耗尽的机制是否也延伸到表达CCR5的CD4T细胞，这些细胞通常表现出更高的细胞激活状态，因此可能不太容易受到流产感染。在特定的目标2中，我们建议确定检测病毒DNA的细胞质传感器(S)。多个传感器可以激活干扰素反应和炎症小体内caspase-1的激活。在具体目标3中，我们建议确定招募caspase-1来处理和释放IL-1并诱导下垂的炎性小体。总之，这些研究将对艾滋病毒导致CD4T细胞耗尽的机制(S)产生新的见解，CD4T细胞是艾滋病的根本问题。这一新的认识可能导致一种全新的艾滋病治疗方法，包括阻断宿主先天免疫反应，促进CD4T细胞死亡和炎症。这种方法可以形成传统抗病毒治疗的强有力的辅助手段，对于表现出广泛耐药性或疾病快速发展的患者可能特别有益。