Neuropathogenesis of Retroviral Infections

逆转录病毒感染的神经发病机制

• 批准号: 10265882
• 负责人: Avindra Nath
• 金额: $ 558万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10265882
• 关键词: 2019-nCoV; Amyotrophic Lateral Sclerosis; Annual Reports; Anti-Retroviral Agents; Antisense Oligonucleotides; Antiviral Therapy; Astrocytes; Autopsy; Biological Assay; Brain; COVID-19; Cell Differentiation process; Cell Line; Cells; Chronic; Chronic Fatigue Syndrome; Clinical Protocols; Clinical Trials; Communicable Diseases; Dengue Infection; Disease; Encephalitis; Endogenous Retroviruses; Fathers; Functional disorder; Gene Activation; Genome; Goals; HIV; HIV Infections; HIV tat Protein; HIV-associated neurocognitive disorder; Immune system; Immunohistochemistry; In Vitro; Individual; Infection; Inflammatory; Lead; Life; Light; Lymphocyte; MRI Scans; Natural History; Neurodegenerative Disorders; Neuroimmune; Neurologic; Neuronal Injury; Neurons; Neuropathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Play; Process; Production; Protocols documentation; Retroviridae; Role; Site; Syndrome; Therapeutic; Tissues; Viral; Viral reservoir; Virus; Virus Activation; Virus Diseases; Virus Latency; antiretroviral therapy; base; brain tissue; coronavirus disease; efficacy testing; env Gene Products; immune activation; in vivo Model; inducible gene expression; nervous system disorder; neuroinflammation; neurotoxic; neurotoxicity; new therapeutic target; prevent; recruit; screening; therapeutic development; trafficking; transmission process; volunteer

The over arching hypothesis is that the brain is an important reservoir for retroviruses because of their ability to infect long lived terminally differentiated cells and viral products released from these cells can cause immune activation and neuronal injury Aim 1: To understand the mechanism of viral persistence in brain While my lab has been studying the mechanism of viral persistence in the brain in the context of HIV infection for several years, we have now studying the same phenomenon in the context of endogenous retroviruses and chronic dengue viral infection in the brain. Lessons learnt from HIV are widely applicable to other viral infections. Recent studies suggest that these viruses may play an important role in the pathophysiology of several neurodegenerative diseases. Hence the study of viral persistence and transmission within the brain is an excellent opportunity to shed new light in the pathophysiology of these diseases and to identify new therapeutic targets. The brain is a unique site of viral latency since the cells have a very low turn over rate and hence viral sequences can reside there for the life of the individual. For example we have found that HIV can be transmitted from cell to cell without complete viral production. We are now developing in vitro and in vivo models to study this phenomenon and determine if other retroviruses and those that cause chronic encephalitis can also similarly persist in the brain and transmit from cell to cell and thus escape the immune system. Aim 2: To investigate the mechanism of neuronal injury by HIV and endogenous retroviruses. neuron diseases. We are studying the mechanism underlying the neurotoxicity and have screened a panel of anti-retroviral drugs against HERV-K. Based on these findings a clinical trial has been initiated for treatment of patients with ALS. Aim 3: To develop therapeutic approaches to prevent viral activation and formation of viral reservoirs in the brain. We have generated cell lines with inducible expression of HIV-Tat protein and the HERV-K virus. These cell lines are being used in high through put screening assays to screen for small pharmacological compounds that suppress their production. We have identified several potential candidates for further characterization. We have also developed antisense molecules to Tat that are being father characterized for their therapeutic potential. In summary, we have shown that astrocytes in the brain are an important reservoir for HIV and that cell to cell contact with lymphocytes is necessary for viral entry and the lysosomal pathway in these cells regulates the intracellular trafficking of the virus and its ultimate ability to successfully infect these cells. Further, we have shown that the HIV protein Tat and the env protein of endogenous retrovirus-K are neurotoxic and we are now studying the underlying mechanisms involved in these effects. We are now developing therapeutic strategies for preventing the activation of these genes. Aim 4: Study of undiagnosed neuroinflammatory diseases. Many patients with neuroinflammatory diseases go undiagnosed for years until proper treatment. We have developed a protocol to study these patients to determine the underlying pathophysiology and initiate appropriate therapy. We have recently identified some new neuroimmune disorders triggered by an infection. Clinical protocols related to this annual report: 1. Natural History Study of Inflammatory and Infectious Diseases of the Nervous System 2. HERV-K Suppression Using Antiretroviral Therapy in Volunteers with Amyotrophic Lateral Sclerosis (ALS) 4.Screening and Recruitment for HIV-associated Neurocognitive Disorders (HAND) Studies Aim 5: To investigate the neuropathogenesis of COVID-19 and develop antiviral therapies: We have initiated the characterization of the neuropathological findings in autopsy brain tissue by immunohistochemistry and postmortem MRI scanning. The focus is to characterize the neuronal damage and immune activation in the brain and determine if there is any evidence of persistent viral infection of the tissues. We have also developed antisense oligonucleotides targeted against the SARS-CoV-2 genome which will be tested for efficacy in an infection assay for further therapeutic development. We are in the process of developing two clinical protocols to study patients with neurological complications of COVID and those who develop a post-viral syndrome similar to myalgic encephalomyelitis/chronic fatigue syndrome.

最重要的假设是，大脑是逆转录病毒的重要储存库，因为它们能够感染长寿的终末分化细胞，而这些细胞释放的病毒产物会导致免疫激活和神经元损伤 目标1：了解病毒在大脑中持续存在的机制 虽然我的实验室一直在研究艾滋病毒背景下病毒在大脑中持续存在的机制 感染已经好几年了，我们现在在内源性背景下研究同样的现象 逆转录病毒和大脑中的慢性登革热病毒感染。从艾滋病毒中吸取的教训广泛 适用于其他病毒感染。最近的研究表明，这些病毒可能在几种神经退行性疾病的病理生理学中发挥重要作用。因此，对病毒在大脑内的持续存在和传播的研究是一个很好的机会，可以为这些疾病的病理生理学提供新的线索，并确定新的治疗靶点。大脑是病毒潜伏的独特部位，因为细胞的更新率非常低，因此病毒序列可以在个体的一生中驻留在那里。例如，我们发现艾滋病毒可以在不完全产生病毒的情况下从一个细胞传播到另一个细胞。我们现在正在开发体外和体内模型来研究这种现象，并确定其他逆转录病毒和引起慢性脑炎的病毒是否也可以类似地在大脑中持续存在并在细胞之间传播，从而逃避免疫系统。 目的2：研究HIV和内源性逆转录病毒损伤神经元的机制。 神经元疾病。我们正在研究神经毒性的机制，并筛选了一组针对 HERV-K 的抗逆转录病毒药物。基于这些发现，一项治疗 ALS 患者的临床试验已经启动。 目标 3：开发预防病毒激活和大脑中病毒库形成的治疗方法。 我们已经产生了可诱导表达 HIV-Tat 蛋白和 HERV-K 病毒的细胞系。 这些细胞系用于高通量筛选试验，以筛选小分子 抑制其产生的药理学化合物。我们已经确定了几个潜在的 进一步表征的候选者。我们还开发了 Tat 的反义分子 父亲的特征是具有治疗潜力。 总之，我们已经证明大脑中的星形胶质细胞是艾滋病毒的重要储存库，并且 细胞与淋巴细胞的接触对于病毒进入是必要的，这些细胞中的溶酶体途径调节病毒的细胞内运输及其成功感染这些细胞的最终能力。此外，我们已经证明，HIV 蛋白 Tat 和内源性逆转录病毒 K 的 env 蛋白具有神经毒性，我们现在正在研究这些效应所涉及的潜在机制。我们现在正在开发防止这些基因激活的治疗策略。 目标 4：研究未确诊的神经炎症性疾病。许多患有神经炎症的患者 疾病多年来一直未被诊断出来，直到得到适当的治疗。我们制定了一项方案来研究这些患者，以确定潜在的病理生理学并启动适当的治疗。我们有 最近发现了一些由感染引发的新的神经免疫性疾病。 与本年度报告相关的临床方案： 1. 神经系统炎症和感染性疾病的自然史研究 2. 在患有肌萎缩侧索硬化症的志愿者中使用抗逆转录病毒疗法抑制 HERV-K 硬化症（ALS） 4.HIV相关神经认知障碍（HAND）研究的筛选和招募 目标 5：研究 COVID-19 的神经发病机制并开发抗病毒疗法： 我们已经开始通过免疫组织化学和死后 MRI 扫描来表征尸检脑组织的神经病理学发现。重点是表征大脑中的神经元损伤和免疫激活，并确定是否有任何组织持续病毒感染的证据。我们还开发了针对 SARS-CoV-2 基因组的反义寡核苷酸，将在感染测定中测试其功效，以进一步开发治疗方法。我们正在制定两项临床方案，以研究患有新冠神经并发症的患者和出现类似于肌痛性脑脊髓炎/慢性疲劳综合症的病毒后综合症的患者。