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

摘要 在全球约4000万艾滋病毒携带者中，约有一半人感染了艾滋病毒 相关神经认知障碍(手)，无论他们是否接受联合治疗 抗逆转录病毒治疗(CART)。手部的轻微形式，在购物车上的艾滋病病毒中最常见， 最终发展成痴呆症。根除艾滋病毒的治疗战略正在进行中，但在 现实是，在可预见的未来，大脑仍将是艾滋病毒的储存库。因此，发展 手部的辅助治疗在促进根除的同时是重要的 战略。另一个要点是针对轻度手的治疗[在此之前 痴呆症]，当治疗更有可能稳定或逆转手。为了更好地实现这一目标， 必须使用实用的、显示认知缺陷和病理的动物模型 与人类温和的手一致，并最好使用复制的艾滋病毒，以便长期 可以对治疗和根除策略的效果进行最佳调查。然而， 目前还没有包含所有这些重要功能的模型。最近，它已经 已经证明，人源化(BLT)小鼠感染艾滋病毒的模型显示出人口贩运 小鼠脑内的细胞，包括T细胞和单核巨噬细胞(MP)，它们是 感染艾滋病毒的类型。人类感染HIV的MP和T细胞已在BLT中被证实 大脑、HIV DNA和RNA可以在大脑中定量，也有类似的小鼠MP反应 这是在人类温和的手中看到的。重要的是，BLT模型展示了长寿的大脑 感染，这使得在足够数量的动物身上测试新的治疗方法 确定在BLT小鼠中具有统计学意义的长期效应和耐受性，也可以 同时用CART治疗。然而，BLT小鼠还没有被证明具有认知能力 缺陷或神经元异常，这是手部的特征。拟议中的研究将检验 使用我们目前短期内建立的技术来治疗BLT小鼠的认知缺陷 SCID鼠标手型。需要监测的基本病理参数将是脑部艾滋病毒 负荷，小鼠和人脑MP炎症活性和神经元树突完整性 额叶皮质、海马体和基底节等重要区域。这些也是 在我们目前的短期手部模型中建立了既定的技术。因此，第一个目标是 根据手的重要特征验证BLT模型，包括认知缺陷和 相关神经元病理学。该提案的第二个主要目的是验证小说 先前显示的治疗在短期手模型和长期手模型中有效 测试手部的有效性、安全性和潜在的脑部艾滋病毒根除。据预测，这是 模型将与提案中详细说明的新治疗方法一起进行验证，提供 为人类临床试验提供直接渠道。

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.