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期存活的终末分化细胞，而从这些细胞释放的病毒产物可以导致免疫激活和神经元损伤。 目的1：了解病毒在脑内持续存在的机制 虽然我的实验室一直在研究HIV病毒在大脑中持续存在的机制 几年来，我们一直在内源性背景下研究同样的现象 逆转录病毒和慢性登革热病毒在大脑中的感染。从艾滋病毒中吸取的教训是广泛的 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，对病毒在脑内持续和传播的研究是揭示这些疾病的病理生理学和确定新的治疗靶点的绝佳机会。大脑是病毒潜伏的独特部位，因为细胞的周转率非常低，因此病毒序列可以在个体的一生中驻留在那里。例如，我们已经发现，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那些导致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，从而逃脱免疫系统。 目的：探讨人类免疫缺陷病毒(HIV)和内源性逆转录病毒对神经元的损伤机制。 神经元病。我们正在研究这种神经毒性的潜在机制，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，已经启动了一项治疗ALS患者的临床试验。 目的3：开发治疗方法，以防止病毒激活和在大脑中形成病毒库。 我们已经建立了可诱导表达HIV-Tat蛋白和Herv-K病毒的细胞系。 这些细胞系正被用于高通量筛选试验，以筛选小细胞 抑制其产生的药理化合物。我们已经确定了几个潜在的 进一步定性的候选者。我们还开发了反义分子来检测 作为父亲的特点是他们的治疗潜力。 综上所述，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，而且 与淋巴细胞的细胞间接触是病毒进入所必需的，这些细胞中的溶酶体途径调节病毒在细胞内的传播及其成功感染这些细胞的最终能力。此外，我们已经证明了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影响的潜在机制。我们现在正在开发防止这些基因激活的治疗策略。 目的4：对未确诊的神经炎性疾病进行研究。许多患者患有神经炎性疾病 在得到适当的治疗之前，疾病会多年得不到诊断。我们已经开发了一种方案来研究这些患者，以确定潜在的病理生理学并开始适当的治疗。我们有 最近发现了一些由感染引发的新的神经免疫疾病。 与本年度报告相关的临床方案： 1.神经系统炎症性和感染性疾病的自然史研究 2.肌萎缩侧索硬化症患者抗逆转录病毒治疗对HERV-K的抑制作用 硬化症(ALS) 4.HIV相关神经认知障碍(HAND)的筛查和招募研究 目的5：研究新冠肺炎的神经发病机制并开发抗病毒治疗方法： 我们已经开始通过免疫组织化学和尸检后MRI扫描来表征尸检脑组织的神经病理结果。重点是确定大脑中神经元损伤和免疫激活的特征，并确定是否有任何证据表明组织中存在持续的病毒感染。我们还开发了针对SARS-CoV-2基因组的反义寡核苷酸，将在感染测试中测试其有效性，以用于进一步的治疗开发。我们正在开发两种临床方案，以研究患有COVID神经系统并发症的患者和那些发展为类似肌痛性脑脊髓炎/慢性疲劳综合征的病毒后综合征的患者。