Defining the Role of Interferon Alpha in HIV Encephalitis

定义干扰素α在艾滋病毒脑炎中的作用

• 批准号: 7284500
• 负责人: ANDREW R SAS
• 金额: $ 3.08万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-05-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7284500
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Adverse effects; Aftercare; Animals; Antibodies; Antiviral Agents; Behavioral; Binding; Brain; Cells; Chronic; Clinical; Complication; Dementia; Endopeptidases; Exhibits; HIV; HIV encephalitis; Hepatitis B; Human; Immune response; Immunohistochemistry; Impaired cognition; In Vitro; Interferon-alpha; Interferons; Lead; Microglia; Modeling; Mononuclear; Mus; Neuraxis; Neuroglia; Neuronal Dysfunction; Neurons; Neurotoxins; Numbers; Pathogenesis; Pathology; Patients; Peptide Hydrolases; Phagocytes; Polymerase Chain Reaction; Production; Research; Role; SCID Mice; Symptoms; Synapses; System; Testing; Thinking; Time; Treatment Protocols; United States; Vaccines; Viral Proteins; Virus Diseases; behavior test; chemokine; cognitive function; cytokine; in vitro Model; in vivo; macrophage; monocyte; mouse model; neutralizing antibody; prevent; response

DESCRIPTION (provided by applicant): The pathogenesis of HIV encephalitis (HIVE), a central nervous system (CNS) complication frequently seen in AIDS patients, is incompletely understood. Since neurons are not infected by HIV, but mononuclear phagocytes are, it is hypothesized that these infected mononuclear phagocytes produce a wide variety of putative neurotoxins that damage neurons. Determining the neurotoxin(s) that result in cognitive dysfunction and HIV pathology can lead to better treatments for patients. We hypothesize that the production of interferon-alpha (IFN?) by HIV infected and activated mononuclear phagocytes in the CNS inhibits neuron function and contributes to HIVE. The role of IFN? in HIVE will be examined in neuron cultures and the HIVE SCID mouse model using immunohistochemistry, real-time PCR, animal behavior testing, and antibody treatment. Neuron cultures exposed to HIV infected mononuclear phagocytes will express morphological changes of decreased dendritic arborization and synaptic connections. Blocking IFN? with neutralizing antibodies will recover these morphological changes. SCID mice inoculated with HIV infected human monocytes exhibit HIVE pathology. An anti- IFN? treatment administered intrathecally in mice will block the effects of IFN? on neurons. This research is important because despite intensive research over the last 25 years, a vaccine or treatment has not been developed to prevent or cure HIV. Therefore, better therapies are needed for treating the complications that arise from HIV infection. By examining the effects of cytokine expression during HIVE this research will help determine the mechanisms that result in abnormal cognitive function and may lead to better treatments for HIV patients in the United States and worldwide.

描述（由申请人提供）：艾滋病毒脑炎（HIVE）是一种常见于艾滋病患者的中枢神经系统（CNS）并发症，其发病机制尚不完全清楚。由于神经元不受HIV感染，但单核吞噬细胞受感染，因此假设这些受感染的单核吞噬细胞产生多种推定的神经毒素，从而损伤神经元。确定导致认知功能障碍和HIV病理学的神经毒素可以为患者提供更好的治疗。我们假设，干扰素-α（IFN？）由HIV感染和激活的单核吞噬细胞在中枢神经系统抑制神经元功能，并有助于HIVE。IFN的作用？将使用免疫组织化学、实时PCR、动物行为测试和抗体处理在神经元培养物和HIVE SCID小鼠模型中检查HIVE中的蛋白质水平。暴露于HIV感染的单核吞噬细胞的神经元培养物将表现出减少的树突分支和突触连接的形态学变化。阻断干扰素？中和抗体将恢复这些形态学变化。用HIV感染的人单核细胞接种的SCID小鼠表现出HIVE病理。抗干扰素？在小鼠鞘内给药的治疗将阻断IFN？在神经元上。这项研究很重要，因为尽管在过去25年里进行了深入的研究，但尚未开发出预防或治愈艾滋病毒的疫苗或治疗方法。因此，需要更好的疗法来治疗艾滋病毒感染引起的并发症。通过检查HIVE期间细胞因子表达的影响，这项研究将有助于确定导致认知功能异常的机制，并可能为美国和全球的HIV患者提供更好的治疗。