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: 8411054
• 负责人: Warner C. Greene
• 金额: $ 32.85万
• 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/8411054
• 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. PUBLIC HEALTH RELEVANCE: These studies seek to understand a fundamental problem in HIV/AIDS, namely how the virus causes the progressive depletion of CD4 T cells. Success in these studies will not only provide new insights into the molecular underpinnings of HIV immunopathogenesis, but also could provide exciting new approaches for preserving CD4 T cells and inhibiting inflammation thereby blocking HIV-induced disease progression. These approaches could be particularly valuable for patients who have failed multiple antiviral drug regimens or who display rapidly progressive disease.

描述（由适用提供）：CD4 T细胞的进行性耗竭是未经治疗的可获得的免疫缺陷综合征（AIDS）的HALMARK，但是CD4 T细胞在HIV感染期间死亡的机制仍然很少理解。 HIV可以直接感染并杀死CD4 T摄氏度，但是在体内存在太少有生效的细胞，无法解释发生的良好CD4 T细胞损失。使用由扁桃体或囊组织形成的原发性人淋巴骨料培养物（HLAC），我们探索了CD4 T细胞在淋巴组织中HIV感染期间如何死亡。我们的研究揭示了几个惊喜，包括：（1）静止的“旁观者” CD4 T细胞，这些细胞不允许X4-Tropic HIV-1允许产物感染，这是由于流产的病毒感染而导致的，由于堕胎病毒感染而导致了不完整的病毒DNA转录本在细胞质中； （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，CD4 T细胞由于针对病毒DNA的强大先天免疫反应而死亡，导致干扰素 - caspase-3和caspase-1的激活产生。 （3）最终，这种反应导致炎性体组装和caspase-1激活触发生物活性IL-1释放并诱导旋转，这是程序性细胞死亡的一种深切的炎症形式。这些事件可以建立一个奇妙的周期，从而垂死的CD4 T细胞释放炎症介质，吸引了新的流产感染和死亡的其他细胞。 4）令人惊讶的是，特定类型的FDA批准的口服磺酰脲药物目前用于治疗II型糖尿病的特定类型的FDA批准类药物可以完全阻断HIV介导的艾滋病毒介导的CD4 T细胞消耗。现在，我们提出了一组关键的新研究。在特定目标1中，我们将测试这种CD4 T细胞定义的这种机制是否还扩展到表达CCR5的CD4 T细胞，该细胞通常显示出更高的细胞激活状态，因此可能不太容易受到流产感染的影响。在特定目标2中，我们建议鉴定检测病毒DNA的细胞质传感器。多个传感器可能会激活干扰素反应和炎症中caspase-1的激活。在特定的目标3中，我们建议识别报告caspase-1的炎性体，以处理和释放IL-1。并诱导凋亡。总之，这些研究将对艾滋病毒诱导的CD4 T细胞的部署（艾滋病中的基本问题）产生新的见解。这种新的理解可能会导致一种全新的治疗方法，用于涉及宿主先天免疫反应的艾滋病，从而促进CD4 T细胞死亡和炎症。这种方法可能形成传统抗病毒疗法的强大辅助手段，可能对表现出广泛的耐药性或疾病快速进展的患者特别有益。 公共卫生相关性：这些研究试图了解艾滋病毒/艾滋病中的基本问题，即病毒如何导致CD4 T细胞的进行性部署。在这些研究中的成功不仅将提供有关HIV免疫发育生成的分子基础的新见解，而且还可以为保存CD4 T细胞提供令人兴奋的新方法，从而抑制感染并阻止HIV诱导的疾病进展。这些方法对于未通过多种抗病毒药物方案或表现出快速进行性疾病的患者特别有价值。