Neurodegeneration in Aged SIV-Infected Primates

描述(申请人提供)：这是一个新的RO1，题为“感染SIV的老年灵长类动物的神经变性”，是我们先前关于SIV脑炎和老年非人类灵长类动物神经退化发病机制研究的直接延伸。在发达国家使用联合活性抗逆转录病毒药物(CART)已导致重型脑炎几乎消失。不幸的是，慢性艾滋病毒感染继续对神经系统造成损害，一种称为艾滋病毒相关神经认知障碍(HAND)的神经认知和运动功能障碍的发病率增加。CART还允许感染艾滋病毒的人存活更长时间，疾控中心预计，到2015年，美国超过一半的艾滋病毒感染者将超过50岁。再加上衰老过程，长期接触艾滋病毒和抗逆转录病毒药物似乎会增加他们患神经和神经精神并发症的风险。在这项应用中，我们建议使用一个公认的慢性慢病毒感染的非人类灵长类动物(NHP)模型，SIV感染猕猴(Rheus Macaque RM)，来模拟老年猕猴(&gt；20岁)，映射神经体征到行为异常，并开始阐明这种衰弱疾病的神经学和免疫学发病机制。虽然没有完美的动物疾病模型，但猴和人类神经系统之间的许多相似之处，SIV和HIV感染之间，以及操纵和监测中枢神经系统(CNS)损伤的能力，使猕猴模型成为这些研究的最佳选择。使用5组SIV感染的RMS和对照的RMS，我们将评估神经认知异常的存在以及病毒抑制在加剧年龄相关性神经变性中的作用。这笔赠款的发现将对老年艾滋病毒感染者的治疗产生直接影响。基于我们过去十年将SIV感染猕猴作为慢性HIV感染模型的经验，以及我们最近对老年NHP中神经炎症的研究(Kofler等人2011(41)见附录)，我们将检验我们的总体假设：无论是否有慢性慢病毒感染，慢性全身推车主要通过中枢神经系统应激和相关的先天性免疫激活来加剧与年龄相关的神经系统损害。我们将评估CART对全身性慢病毒感染的积极抑制是否会加剧与年龄相关的认知异常和与β淀粉样蛋白相关的神经病理(例如斑块、缠结、异常tau磷酸化或β淀粉样寡聚)。或者，即使存在病毒抑制或仅作为CART的结果，HAND也可能持续存在。在我们的第二个具体目标中，我们将使用最先进的定量神经病理学分析来阐明手的病理基础。在猿猴模型中了解神经功能障碍的发病机制将有助于确定减轻人类疾病的干预途径。

DESCRIPTION (provided by applicant): This is a new RO1 entitled "Neurodegeneration in aged SIV-infected primates" that is a direct extension of our previously investigations in the pathogenesis of SIV encephalitis and neurodegeneration in aged non-human primates. Use of combined active antiretrovirals (CART) in developed countries has led to a near disappearance of severe encephalitis. Unfortunately chronic HIV infection continues to exact a toll on the nervous system with increased prevalence of a spectrum of neurocognitive and motor dysfunctions termed HIV-associated neurocognitive disorders (HAND). CART has also permitted people to survive longer with HIV infection and the CDC projects that by 2015 over half of HIV infected individuals in the US will be over the age of 50. Coupled with the aging process, the extended exposure to both HIV and antiretroviral drugs appears to increase their risk of neurologic and neuropsychiatric complications. In this application we propose to use a well-established non-human primate (NHP) model of chronic lentiviral infection, SIV infection of Macaca mulatta (Rhesus Macaque RM), to model HAND in aged macaques (>20 years old), map the neurological signs to behavioral abnormalities and begin to elucidate the neurological and immunological pathogenesis of this debilitating disease. While no animal disease model is perfect, numerous similarities between simian and human nervous systems, between SIV and HIV infection and the capacity to manipulate and monitor central nervous system (CNS) damage, make the macaque model optimal for these studies. Using 5 groups of SIV infected and control RMs, we will assess the presence of neurocognitive abnormalities and the role of viral suppression in exacerbating age related neurodegeneration. Findings from this grant will have immediate implications on the treatment of aged HIV infected humans. Building upon our previous decade of experience with SIV infection of macaques as a model of chronic HIV infection and our recent studies of neuroinflammation in aged NHPs (Kofler et al 2011 (41) see appendix), we will test our overarching hypothesis that: chronic systemic CART with or without chronic lentiviral infection exacerbates age related damage to the nervous system principally through CNS stress and associated innate immune activation. We will assess whether aggressive suppression of systemic lentiviral infection with CART exacerbates age related cognitive abnormalities and beta amyloid related neuropathology (e.g. plaques, tangles, abnormal tau phosphorylation or beta amyloid oligomeres). Alternatively, HAND may persist even in the presence of viral suppression or as a result of CART alone. In our second specific aim we will use state of the art quantitative neuropathological analysis to elucidate the pathological substrate of HAND. Knowledge of the pathogenesis of neurological dysfunction in the simian model will help define pathways for intervention to mitigate the human disease.