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（由申请人提供）：CD 4 T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）的一个标志，但对HIV感染期间CD 4 T细胞死亡的机制仍知之甚少。HIV可以直接感染和杀死CD 4 T细胞，但是体内很少有有效感染的细胞，无法解释发生的大量CD 4 T细胞损失。利用扁桃体或脾组织形成的原代人淋巴聚集体培养物（HLAC），我们探索了淋巴组织中HIV感染期间CD 4 T细胞是如何死亡的。我们的研究已经揭示了几个令人惊讶的结果，包括：（1）静止的“旁观者”CD 4 T细胞，其不允许嗜X4的HIV-1的生产性感染，由于伴随着不完整的病毒DNA转录物在细胞质中的积累的失败的病毒感染而大量死亡;（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，CD 4 T细胞由于针对病毒DNA发起的强大的先天免疫应答而死亡，导致干扰素的产生以及半胱天冬酶-3和半胱天冬酶-1的激活;（3）最终，这种应答导致炎性小体组装和半胱天冬酶-1激活，触发生物活性IL-1的释放。以及诱导焦亡，一种强烈的炎症形式的程序性细胞死亡。这些事件可以建立恶性循环，由此垂死的CD 4 T细胞释放炎性介质，吸引额外的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CD 4 T细胞耗竭通过焦亡可以被目前用于治疗II型糖尿病的特定类别的FDA批准的口服磺酰脲类药物完全阻断。我们现在提出一系列关键的新研究。在特定目标1中，我们将测试这种CD 4 T细胞耗竭机制是否也延伸到CCR 5表达的CD 4 T细胞，这些细胞通常表现出更高的细胞活化状态，因此可能对流产感染不太敏感。在具体目标2中，我们提出鉴定检测病毒DNA的细胞质传感器。多个传感器可以激活干扰素反应和炎症小体内的半胱天冬酶-1的激活。在具体目标3中，我们提出鉴定招募caspase-1以加工和释放IL-1并诱导细胞凋亡的炎性小体。总之，这些研究将对HIV诱导的CD 4 T细胞耗竭的潜在机制产生新的见解，这是AIDS的基本问题。这种新的理解可能会导致一种全新的艾滋病治疗方法，包括阻断促进CD 4 T细胞死亡和炎症的宿主先天免疫反应。这种方法可以成为传统抗病毒治疗的有力辅助手段，对于表现出广泛耐药性或疾病快速进展的患者可能特别有益。 公共卫生相关性：这些研究试图了解艾滋病毒/艾滋病的一个基本问题，即病毒如何导致CD 4 T细胞的逐渐耗尽。这些研究的成功不仅将为HIV免疫发病机制的分子基础提供新的见解，而且还可以为保护CD 4 T细胞和抑制炎症从而阻断HIV诱导的疾病进展提供令人兴奋的新方法。这些方法对于多种抗病毒药物治疗失败或疾病进展迅速的患者特别有价值。