Validating a Humanized Mouse HIV Model for Cognitive Deficits and Novel Treatments

验证人源化小鼠 HIV 模型的认知缺陷和新疗法

• 批准号: 10513293
• 负责人: WILLIAM R TYOR
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513293
• 关键词: Aging; Alzheimer' s Disease; Animal Model; Animals; BLT mice; Basal Ganglia; Behavior; Biological; Brain; Cells; Cessation of life; Clinical; Clinical Trials; Cognitive deficits; DNA; Data; Dementia; Development; Disease model; Exhibits; Flow Cytometry; Future; HIV; HIV Infections; HIV-associated neurocognitive disorder; Hippocampus; Human; Individual; Infection; Infiltration; Inflammatory; Legal patent; Long-Term Effects; Memory impairment; Methods; Modeling; Monitor; Mononuclear; Mus; Neurons; Pathologic; Pathology; Patients; Persons; Phagocytes; Publishing; RNA; Radial; Reaction; Rheumatoid Arthritis; Risk; SCID Mice; Safety; Stroke; T-Lymphocyte; Techniques; Testing; Time; Validation; Veterans; Water; Work; aging population; antiretroviral therapy; arm; cell type; cognitive testing; comorbidity; efficacy testing; frontal lobe; glial activation; humanized mouse; inhibitor; mouse model; novel; object recognition; predictive modeling; screening; trafficking; treatment effect; treatment strategy

Abstract Approximately half of the roughly 40 million people with HIV (PHIV) worldwide develop HIV associated neurocognitive disorders (HAND), regardless of whether they receive combined antiretroviral therapy (cART). Mild forms of HAND, which are most common in PHIV on cART, ultimately progress to dementia. Treatment strategies to eradicate HIV are ongoing, but in reality the brain will remain an HIV reservoir for the foreseeable future. Therefore, developing adjunctive treatments for HAND is important while simultaneously advancing eradication strategies. Another important point is targeting treatments to mild forms of HAND [prior to dementia], when treatment is more likely to stabilize or reverse HAND. To best accomplish this, an animal model must be used that is practical, displays cognitive deficits and pathology consistent with mild HAND in humans, and preferably employs replicating HIV so that long-term effects of treatments and eradication strategies can be optimally investigated. However, currently there is no model that incorporates all of these important features. Recently it has been shown that humanized (BLT) mouse models of HIV infection exhibit trafficking of human cells to mouse brain, including T cells and mononuclear phagocytes (MP), which are the cell types infected by HIV. HIV-infected human MP and T cells have been demonstrated in BLT brains, HIV DNA and RNA can be quantitated in brain, and there is a mouse MP reaction similar that seen in humans with mild HAND. Importantly the BLT model exhibits long lived brain infection, which enables testing of novel treatments in sufficient numbers of animals to determine statistically significant, prolonged effects and tolerability in BLT mice that can also be simultaneously treated with cART. However, BLT mice have not been shown to have cognitive deficits or neuronal abnormalities, which are hallmarks of HAND. The proposed studies will test BLT mice for cognitive deficits using techniques that are established in our current short term SCID mouse HAND model. Essential pathological parameters to be monitored will be brain HIV load, mouse and human brain MP inflammatory activity, and neuronal dendritic integrity in important regions such as frontal cortex, hippocampus and the basal ganglia. These are also established techniques in our current short-term HAND model. Therefore, the first aim is to validate the BLT model according to important features of HAND including cognitive deficits and associated neuronal pathology. The second major aim of the proposal is to validate novel treatments previously shown to be effective in the short-term HAND model with long-term testing for efficacy in HAND, safety and potentially brain HIV eradication. It is predicted that this model will be validated along with novel treatments as detailed in the proposal, providing a direct conduit to human clinical trials.

摘要 全世界约4000万艾滋病毒感染者中，约有一半会感染艾滋病毒 相关的神经认知障碍（HAND），无论他们是否接受联合治疗， 抗逆转录病毒疗法（cART）。轻度HAND，在接受cART治疗的PHIV中最常见， 最终发展为痴呆症。根除艾滋病毒的治疗战略正在进行中，但在 事实上，在可预见的未来，大脑仍将是艾滋病毒的储存库。因此开发 HAND的连续治疗很重要，同时推进根除 战略布局另一个要点是针对轻度HAND的治疗[之前] 治疗更有可能稳定或逆转HAND。为了最好地实现这一点， 必须使用实用的、显示认知缺陷和病理的动物模型 与人类中的轻度HAND一致，并且优选地采用复制HIV， 可以最佳地研究治疗和根除策略的效果。然而，在这方面， 目前还没有一种模式能够包含所有这些重要特征。近来这个字 已经显示，HIV感染的人源化（BLT）小鼠模型表现出人类的运输， 细胞，包括T细胞和单核吞噬细胞（MP），这是细胞 感染艾滋病毒的类型。HIV感染的人MP和T细胞已在BLT中得到证实 脑内可定量HIV DNA和RNA，与小鼠脑内有MP反应相似 这是在人类身上看到的。重要的是，BLT模型表现出长寿的大脑 感染，这使得能够在足够数量的动物中测试新的治疗方法， 在BLT小鼠中确定统计学上显著的、长期的作用和耐受性， 同时进行cART治疗。然而，BLT小鼠没有表现出认知能力， 缺陷或神经元异常，这是HAND的标志。拟议的研究将测试 使用我们目前短期内建立的技术， SCID小鼠HAND模型。需要监测的基本病理参数将是脑艾滋病毒 负荷，小鼠和人脑MP炎症活性，和神经元树突的完整性， 重要的区域，如额叶皮层，海马和基底神经节。这些也是 在我们目前的短期HAND模型中建立的技术。因此，第一个目标是 根据HAND的重要特征（包括认知缺陷）验证BLT模型， 相关的神经病理学。该提案的第二个主要目的是验证新的 先前在短期HAND模型中显示有效的治疗， 测试手部功效、安全性和潜在的脑部艾滋病毒根除。据预测， 该模型将沿着与提案中详述的新治疗方法一起进行验证， 直接用于人体临床试验