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）：CD4 T 细胞的逐渐耗竭是未经治疗的获得性免疫缺陷综合征 (AIDS) 的标志，但 HIV 感染期间 CD4 T 细胞死亡的机制仍知之甚少。然而，体内存在的有效感染细胞太少，无法解释发生的大量 CD4 T 细胞损失。我们探索了 CD4 T 细胞在淋巴组织中的 HIV 感染过程中如何死亡，我们的研究揭示了一些令人惊讶的结果，包括：（1）静止的“旁观者”CD4 T 细胞，它们不允许 X4 嗜性 HIV-1 的有效感染。由于病毒感染失败而导致大量死亡，并伴随着不完整的病毒 DNA 转录物在细胞质中的积累；(2) 死亡不是由这些 DNA 或其他病毒产物的毒性作用引起的；而是 CD4 T 细胞因此而死亡；的一个针对病毒 DNA 发起强大的先天免疫反应，从而产生干扰素-¿ caspase-3 和 caspase-1 的激活；(3) 最终，这种反应导致炎症小体组装和 caspase-1 激活，从而触发生物活性 IL-1 的释放细胞焦亡是一种强烈炎症形式的程序性细胞死亡，这些事件会形成恶性循环，因此垂死的 CD4 T 细胞会释放炎症介质，吸引更多细胞进行新一轮的流产感染和死亡 4) 令人惊讶的是，HIV 介导的； FDA 批准的目前用于治疗 II 型糖尿病的特定类别的口服磺酰脲类药物可以完全阻断焦亡引起的 CD4 T 细胞耗竭。具体目标 1，我们将测试这种 CD4 T 细胞耗竭机制是否也适用于表达 CCR5 的 CD4 T 细胞，这些细胞通常表现出较高的细胞激活状态，因此可能不太容易受到流产感染的影响。为了识别检测病毒 DNA 的细胞质传感器，多个传感器可能会激活炎症小体内的干扰素反应和 caspase-1 的激活。募集 caspase-1 来处理和释放 IL-1 的炎症小体这些研究将共同​​对 HIV 引起的 CD4 T 细胞耗竭的机制产生新的见解——这是艾滋病的根本问题，这一新的认识可能会导致一种完全涉及艾滋病毒阻断的新治疗方法。促进 CD4 T 细胞死亡和炎症的宿主先天免疫反应，这种方法可以形成传统抗病毒治疗的强有力的辅助手段，并且可能对表现出广泛耐药性或疾病快速进展的患者特别有益。