Neurodegeneration in Aged SIV-Infected Primates

描述（由申请人提供）：这是一篇新的RO1，题为“老年SIV感染灵长类动物的神经变性”，是我们之前对老年非人灵长类动物SIV脑炎和神经变性发病机制的研究的直接延伸。在发达国家，联合使用活性抗逆转录病毒药物（CART）已导致严重脑炎几乎消失。不幸的是，慢性艾滋病毒感染继续对神经系统造成损害，随着被称为艾滋病毒相关神经认知障碍（HAND）的一系列神经认知和运动功能障碍的患病率增加。CART还使感染艾滋病毒的人活得更长，疾病预防控制中心预计，到2015年，美国一半以上的艾滋病毒感染者将超过50岁。随着年龄的增长，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。在这个应用中，我们建议使用一个成熟的非人类灵长类动物（NHP）慢性慢病毒感染模型，猕猴猴（Rhesus Macaque RM）的SIV感染，来模拟老年猕猴（bb0 - 20岁）的HAND，将神经体征映射到行为异常，并开始阐明这种使人衰弱的疾病的神经和免疫发病机制。虽然没有动物疾病模型是完美的，但猿猴和人类神经系统之间、SIV和HIV感染之间以及操纵和监测中枢神经系统（CNS）损伤的能力之间的许多相似之处，使猕猴模型成为这些研究的最佳选择。使用5组SIV感染和对照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神经变性中的作用。这笔拨款的研究结果将对老年艾滋病毒感染者的治疗产生直接影响。基于我们过去十年对猕猴SIV感染作为慢性HIV感染模型的经验，以及我们最近对老年NHPs神经炎症的研究（Kofler等人2011年（41）见附录），我们将验证我们的总体假设：慢性系统性CART伴或不伴慢性慢病毒感染，主要通过中枢神经系统应激和相关的先天免疫激活加剧与年龄相关的神经系统损伤。我们将评估CART对全身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学（如斑块、缠结、异常的tau磷酸化或β -淀粉样蛋白寡聚物）。另外，即使存在病毒抑制或仅由于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HAND的病理基础。在类人猿模型中了解神经功能障碍的发病机制将有助于确定干预途径以减轻人类疾病。

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.