eCD4-mediated control of SIV infection in the brain

eCD4 介导的脑部 SIV 感染控制

• 批准号: 10698442
• 负责人: Michael R. Farzan
• 金额: $ 91.41万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698442
• 关键词: AIDS dementia; Affinity; Animals; Antibodies; Astrocytes; Behavior; Binding; Binding Sites; Biological; Biological Markers; Biological Products; Blood - brain barrier anatomy; Brain; CCR5 gene; CXCR4 gene; Cells; Central Nervous System; Central Nervous System Diseases; Central Nervous System Infections; Cerebrospinal Fluid; Clinical Trials; Compensation; Consequences of HIV; DNA cassette; Disease Progression; Drug Kinetics; Gene Transduction Agent; HIV; HIV Infections; HIV antiretroviral; HIV-associated neurocognitive disorder; Human; Immunoglobulin G; Infection; Infection Control; Infusion procedures; Intramuscular; Intravenous; Laboratories; Left; Life; Lymphocyte; Macaca; Macaca mulatta; Macaca nemestrina; Macrophage; Measures; Mediating; Methods; Microglia; Modeling; Monitor; Mus; Muscle; Neurofilament Proteins; Neurologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Plasma; Predisposition; Prevalence; Protein Secretion; Recombinant adeno-associated virus (rAAV); Regimen; Reproducibility; Research Personnel; SIV; SIV encephalitis; Safety; Severities; Side; Skeletal Muscle; Testing; Therapeutic; Toxic effect; Viral Load result; Viremia; Virus; adeno-associated viral vector; antiretroviral therapy; brain tissue; cell type; co-infection; compliance behavior; cost; detection limit; efficacy study; experience; experimental study; expression vector; fitness; inhibitor; monocyte; neuroAIDS; neurotropic; neutralizing antibody; nonhuman primate; peptidomimetics; prevent; promoter; receptor; receptor expression; side effect; simian human immunodeficiency virus; small molecule; social stigma; AIDS dementia; Affinity; Animals; Antibodies; Astrocytes; Behavior; Binding; Binding Sites; Biological; Biological Markers; Biological Products; Blood - brain barrier anatomy; Brain; CCR5 gene; CXCR4 gene; Cells; Central Nervous System; Central Nervous System Diseases; Central Nervous System Infections; Cerebrospinal Fluid; Clinical Trials; Compensation; Consequences of HIV; DNA cassette; Disease Progression; Drug Kinetics; Gene Transduction Agent; HIV; HIV Infections; HIV antiretroviral; HIV-associated neurocognitive disorder; Human; Immunoglobulin G; Infection; Infection Control; Infusion procedures; Intramuscular; Intravenous; Laboratories; Left; Life; Lymphocyte; Macaca; Macaca mulatta; Macaca nemestrina; Macrophage; Measures; Mediating; Methods; Microglia; Modeling; Monitor; Mus; Muscle; Neurofilament Proteins; Neurologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Plasma; Predisposition; Prevalence; Protein Secretion; Recombinant adeno-associated virus (rAAV); Regimen; Reproducibility; Research Personnel; SIV; SIV encephalitis; Safety; Severities; Side; Skeletal Muscle; Testing; Therapeutic; Toxic effect; Viral Load result; Viremia; Virus; adeno-associated viral vector; antiretroviral therapy; brain tissue; cell type; co-infection; compliance behavior; cost; detection limit; efficacy study; experience; experimental study; expression vector; fitness; inhibitor; monocyte; neuroAIDS; neurotropic; neutralizing antibody; nonhuman primate; peptidomimetics; prevent; promoter; receptor; receptor expression; side effect; simian human immunodeficiency virus; small molecule; social stigma

PROJECT SUMMARY Combined antiretroviral therapy (ART) has revolutionized the treatment of HIV but ART regimens are not without drawbacks. Cost, the need for daily administration, side effects, and social stigma all contribute to reduced patient compliance. Moreover, despite treatment, some 15-55% of people living with HIV will develop some form of HIV-associated neurocognitive disorder (HAND). Because of these problems with ART regimens, we and many other investigators have been studying the use of recombinant adeno-associated virus (rAAV) gene therapy vectors to deliver antibodies and other HIV therapeutics to people living with HIV. Because expression from these vectors is essentially permanent; patients could be protected for life from HIV infections with only a single AAV treatment (i.e. a ‘functional’ cure). Although numerous nonhuman primate experiments and two human clinical trials have been conducted to study the use of AAV for functional cure, however, we are unaware of any efforts to determine whether or not rAAV-expressed biologics can prevent or treat HAND. We have developed an anti-HIV biologic called eCD4, a fusion of CD4-Ig with a carboxy-terminal co-receptor (CCR5/CXCR4) mimetic peptide. We hypothesize that eCD4 is uniquely suited to preventing replication of the neurotropic strains of HIV that preferentially infect the brain (macrophage-tropic isolates) because these viruses necessarily evolve high affinity for CD4 to compensate for the low abundance of CD4 on macrophages and microglia. The organizing hypothesis of this project, then, is to determine if rAAV-delivered eCD4, either expressed from the periphery or within the central nervous system, can prevent or treat HAND. To test this hypothesis, we will use a pigtail macaque model of SIV-induced central nervous system disease, developed in our laboratories, in which co-infection with an immunosuppressive swarm (SIV/DeltaB670) and neurotropic clone (SIV/17E-Fr) establishes a highly reproducible CNS infection. Animals will be treated with ART until aviremic and rAAV will be used to deliver a pigtail macaque version of eCD4 to skeletal muscle and/or brain tissue. ART will be withdrawn to determine whether or not rAAV/eCD4 can prevent the re-emergence of CNS viremia. If successful, these studies may open new avenues to the functional cure of HIV and treatment of HAND.

项目摘要 联合抗逆转录病毒疗法（ART）彻底改变了艾滋病毒的治疗，但艺术方案不是 没有缺点。成本，对日常管理的需求，副作用和社会污名都有助于 降低患者的依从性。此外，目的地治疗，大约15-55％的艾滋病毒患者会发展 某种形式的HIV相关神经认知障碍（HARD）。 由于艺术方案的这些问题，我们和许多其他研究人员一直在研究使用 重组腺癌相关病毒（RAAV）基因疗法载体，以提供抗体和其他HIV 对艾滋病毒感染者的治疗。因为这些向量的表达本质上是永久的； 只有一种AAV治疗的患者可以保护患者终身免受HIV感染（即A功能性' 尽管已经进行了许多非人类灵长类动物实验和两项人类临床试验 但是，为了研究AAV用于功能治疗的使用，我们没有意识到任何努力来确定是否或 不表达RAAV的生物制剂可以预防或治疗手。 我们开发了一种称为ECD4的抗HIV生物学，CD4-Ig与羧基末端共受体融合 （CCR5/CXCR4）模拟肽。我们假设ECD4非常适合防止复制 优先感染大脑（巨噬细胞 - 肉体分离株）的HIV的神经性菌株，因为这些 病毒必然会进化对CD4的高亲和力，以补偿巨噬细胞上CD4的低丰度 和小胶质细胞。 因此 外围神经系统或中枢神经系统内可以防止或治疗手。为了检验这一假设，我们 将使用SIV引起的中枢神经系统疾病的辫子猕猴模型 实验室，其中与免疫抑制群（SIV/Deltab670）和神经性克隆共同感染 （SIV/17E-FR）建立了高度可再现的中枢神经系统感染。动物将用艺术治疗直到无毒 Raav将用于将锯齿猕猴的ECD4提供给骨骼肌肉和/或脑组织。 将撤回ART，以确定RAAV/ECD4是否可以防止CNS病毒血症的重新出现。 如果成功，这些研究可能会为HIV的功能治疗和手治疗提供新的途径。