Quantifying cognitive-motor decline in FIV-infected cats

描述(申请人提供)：人类免疫缺陷病毒(HIV)感染中枢神经系统(CNS)仍然是一个严重的问题，因为感染持续存在，进行性神经退化，并导致认知能力下降。尽管抗逆转录病毒药物减缓了中枢神经系统疾病的进展，但随着艾滋病毒感染者的寿命延长，预计将造成越来越严重的损失。开发旨在防止神经元损伤的治疗策略是必要的，但由于缺乏概括导致艾滋病毒感染神经发病机制的动物模型而受到阻碍。猴免疫缺陷病毒感染猕猴可能是目前最好的模型，但价格昂贵，而且受到动物可获得性的限制。猫免疫缺陷病毒(FIV)提供了慢病毒神经致病的另一种模型，它概括了人类艾滋病毒感染的所有基本方面。然而，该模型的实用性因其缓慢的中枢神经系统疾病进展以及缺乏跟踪疾病进展的行为评估范例而降低。我们已经开发了一种方案来增加猫的CNS FIV病毒负担，以促进CNS疾病的进展。这项研究的目的是确认特定的行为测试，这些测试将被用于敏感和可靠地监测这些感染FIV的猫的疾病进展。CanCog Technologies最近开发的多功能猫科动物行为测试功能为设计一种对FIV感染猫的认知运动缺陷敏感的行为测试组件提供了机会。使用原型设备进行的初步观察和对活动的视频监测表明，接种后6个月就可能检测到显著的行为缺陷，12个月时观察到逐渐变化。预计这些测试提供了神经疾病进展的敏感指标，可用于评估治疗干预的效果。拟议的研究将在感染后1周、5个月、10个月和15个月对脑内感染嗜神经性FIV的猫和假感染的匹配对照组进行行为测试。将同时测量血浆FIV、脑脊液FIV和淋巴细胞亚群，以提供对疾病进展的每个方面的全面评估，并与行为结果进行比较。行为数据应该提供神经疾病进展的基本特征，这是实施适合于治疗测试的猫模型所需的。 公共卫生相关性：猫免疫缺陷病毒感染提供了一个很好的自然感染模型和类似于人类艾滋病毒感染的神经发病机制。使用这一模型评估疾病机制和测试新疗法的一个重要障碍是难以准确跟踪早期中枢神经系统疾病的进展。本申请中建议的行为测量的使用和验证将提供一种敏感的评估工具，能够量化感染后1-2年内的缺陷。所提出的范例的发展将极大地促进将新的治疗方案转化为有效的艾滋病毒神经发病的体内模型。

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) remains a serious problem due to the persistence of infection, progressive neural degeneration, and resulting cognitive decline. The progression of CNS disease, although slowed by antiretrovirals, is expected to exert an increasingly heavy toll as patients with HIV live longer. The development of therapeutic strategies designed to protect against neuronal damage are needed but have been hindered by a lack of animal models that recapitulate the conditions that lead to neuropathogenesis in HIV infection. Simian immunodeficiency virus infection of macaques is perhaps the best model available but is expensive and restricted by availability of animals. Feline immunodeficiency virus (FIV) offers an alternative model of lentiviral neuropathogenesis which recapitulates all essential aspects of HIV infection in humans. However, the utility of this model has been reduced by its slow CNS disease progression and the absence of behavioral assessment paradigms to track disease progression. We have developed a protocol to increase CNS FIV viral burden in the cats to facilitate CNS disease progression. The objective of this study is to confirm specific behavioral tests that will be used to sensitively and reliably monitor the progression of the disease in these FIV-infected cats. The recent development of versatile feline behavioral testing capabilities by CanCog Technologies has provided the opportunity to design a behavioral test battery sensitive to the cognitive-motor deficits in FIV infected cats. Preliminary observations using a prototype apparatus and video monitoring of activity have indicated that significant behavioral deficits may be detected as early as six months post-inoculation with progressive changes observed at 12 months. It is anticipated that these tests provide sensitive measures of neurological disease progression that can be used to assess the efficacy of therapeutic interventions. The proposed studies will apply behavioral tests to cats infected intracranially with neurotropic FIV and sham-infected matched controls, at 1 week, and 5, 10 and 15 months post-infection. Parallel measures of plasma FIV, CSF FIV and lymphocyte subsets will be taken to provide a comprehensive assessment of each aspect of disease progression, to be compared to behavioral findings. The behavioral data should provide the basic characterization of neurological disease progression needed for the implementation of a feline model suitable for testing of therapeutics. PUBLIC HEALTH RELEVANCE: Feline immunodeficiency virus infection provides an excellent natural model of infection and neuropathogenesis similar to HIV infection in humans. A significant barrier to the use of this model for evaluation of disease mechanisms and testing of new therapeutics is the difficulty of accurately tracking early CNS disease progression. The use and validation of behavioral measures as proposed in this application will provide a sensitive assessment tool capable of quantifying deficits within 1-2 years of infection. Development of the proposed paradigms will greatly facilitate the translation of new therapeutic regimens to a valid in vivo model of HIV neuropathogenesis.