Combination Antiretroviral Therapy and inflammation/neurodegeneration in the CNS

抗逆转录病毒治疗与中枢神经系统炎症/神经变性的联合治疗

基本信息

批准号：
7321669
负责人：
M CHRISTINE ZINK
金额：
$ 25.17万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7321669
关键词：
Acquired Immunodeficiency Syndrome Acute Adverse effects Animals Anti-Retroviral Agents Antiviral Agents Antiviral Therapy Astrocytes Astrocytosis Autopsy Biological Models Blood Blood - brain barrier anatomy Brain CD8B1 gene Central Nervous System Diseases Characteristics Chronic Conflict (Psychology)Data Development Disease Dose Drug usage Effector Cell Encephalitis Endothelial Cells Equilibrium Generations Genotype HIV HIV Envelope Protein gp120 HIV Infections Highly Active Antiretroviral Therapy Human Immune response Immunosuppression Incidence Individual Infection Infiltration Inflammation Inflammatory Intercellular adhesion molecule 1 Lesion Lymphoid Tissue Macaca Macrophage Activation Microglia Modeling Nelfinavir Nerve Degeneration Nervous System Physiology Neurons Patients Peripheral Pharmaceutical Preparations Plasma Production Protease Inhibitor Proteins Psychomotor Impairments Reporting Reverse Transcriptase Inhibitors Role SIV Schedule Signaling Molecule Staging T-Lymphocyte Therapeutic Therapeutic immunosuppression Time Tissue Sample Today Viral Viral Load result Viral Proteins Viral load measurement Virus Virus Replication Withdrawal antiretroviral therapy base chemokine cognitive function cytokine day design improved macrophage neurotoxic non-nucleoside reverse transcriptase inhibitors novel therapeutics pinacolyl methylphosphonic acid programs viral DNA

项目摘要

HIV replication in the CNS results in widespread activation of microglia and astrocytosis and neuronal damage. Highly active antiretroviral therapy (HAART) decreases plasma and in some cases CSF viral load, delays the onset of immunosuppression (AIDS) and improves cognitive function in HIV-infected individuals. However, there is evidence that HAART has been less effective in lowering virus replication in the CNS than in the blood, perhaps because not all drugs cross the blood-brain barrier. Thus, the brain may be a reservoir where HIV remains latent and undergoes resurgent replication upon cessation of antiretroviral therapy, either because of unacceptable side effects or noncompliance. In this Project a well-characterized SIV/macaque model will be used to examine the effects of combination antiretroviral therapy (CART) with a non-nucleoside reverse transcriptase inhibitor (PMPA) and a protease inhibitor (nelfinavir) on CNS virus replication, inflammation and neurodegeneration. Our hypothesis is that combination antiretroviral therapy (CART) with drugs that suppress viral load in the plasma to below detectable levels will only partly suppress virus replication in the brain, and that low-level virus replication in the CNS will result in production of neurotoxic viral and cellular products and only partial amelioration of neurodegeneration. We further hypothesize that upon cessation of antiviral therapy there will be rapid resurgence of CNS virus replication with development of inflammation and neurodegeneration. Aim 1 will determine the extent to which CART treatment of SIVinfected macaques suppresses CNS expression of viral neurotoxic proteins, infiltration and/or activation of macrophages,microglia, astrocytes and endothelial cells, and production of proinflammatory/neurotoxic chemokines and cytokines in the brain. Aim 2 will determine whether CART normalizes the homeostatic balance between expression of proapoptotic and antiapoptotic signaling molecules in the brain, and inhibits the development of acute and/or chronic neurodegeneration Aim 3 will determine whether there is independent replication of specific genotypes in the CNS when virus replication is suppressed in the periphery. Aim 4 will determine whether cessation of antiretroviral therapy results in more rapid development of CNS inflammation and neurodegeneration and whether renewed virus replication in the CNS after withdrawal of antiretroviral drugs occurs from pre-existing virus and/or renewed entry of virus from the periphery.

HIV 在中枢神经系统中的复制导致小胶质细胞广泛激活、星形细胞增多和神经元损伤。高效抗逆转录病毒疗法 (HAART) 可以降低血浆病毒载量，在某些情况下还可以降低脑脊液病毒载量，延缓免疫抑制 (AIDS) 的发作，并改善 HIV 感染者的认知功能。然而，有证据表明HAART在降低中枢神经系统中的病毒复制方面不如血液中的病毒复制有效，这可能是因为并非所有药物都能穿过血脑屏障。因此，大脑可能是艾滋病毒的储存库，艾滋病毒在其中保持潜伏，并在抗逆转录病毒治疗停止后重新复制，无论是由于不可接受的副作用还是不依从性。在该项目中，将使用一个充分表征的SIV/猕猴模型来检查联合抗逆转录病毒疗法（CART）与非核苷逆转录酶抑制剂（PMPA）和蛋白酶抑制剂（奈非那韦）对中枢神经系统病毒复制的影响，炎症和神经变性。我们的假设是，联合抗逆转录病毒疗法（CART）与将血浆中的病毒载量抑制到低于可检测水平的药物只能部分抑制大脑中的病毒复制，而中枢神经系统中的低水平病毒复制将导致神经毒性病毒的产生和细胞产物，并且仅部分改善神经退行性变。我们进一步假设，停止抗病毒治疗后，中枢神经系统病毒复制将迅速恢复，并出现炎症和神经变性。目标 1 将确定 CART 治疗 SIV 感染的程度猕猴抑制中枢神经系统病毒神经毒性蛋白的表达，巨噬细胞、小胶质细胞、星形胶质细胞和内皮细胞的浸润和/或激活，以及大脑中促炎/神经毒性趋化因子和细胞因子的产生。目标 2 将确定 CART 是否使大脑中促凋亡和抗凋亡信号分子表达之间的稳态平衡正常化，并抑制急性和/或慢性神经变性的发展。目标 3 将确定当病毒感染时，中枢神经系统中是否存在特定基因型的独立复制。复制在外围受到抑制。目标4将确定停止抗逆转录病毒治疗是否会导致中枢神经系统炎症和神经变性更快发展，以及撤回抗逆转录病毒药物后中枢神经系统中的新病毒复制是否来自先前存在的病毒和/或病毒从外周重新进入。