Studies of Retinopathy of AIDS in the HAART Era

描述(申请人提供)：在当前有效的抗逆转录病毒治疗的时代，众所周知，艾滋病毒患者既会发展为感染性(典型的巨细胞病毒视网膜炎)，也会发展为非传染性(视网膜微血管阻塞，最常被视为棉毛点)形式的视网膜病变。美国有100多万艾滋病毒阳性者，这种疾病对少数族裔的影响不成比例。目前，非感染性视网膜病变很常见，我们已经证明，即使在没有明显感染性视网膜炎的眼睛中，它也是导致视力丧失的原因。HIV患者的视网膜内部存在结构性损伤，这与视力丧失和功能障碍有关。感染性巨细胞病毒视网膜炎仍然是抗药性巨细胞病毒视网膜炎导致严重视力丧失的原因之一，这些患者的反应不佳或不能可靠地接受HAART治疗。我们将使用新的方法来分析HIV患者的视网膜结构和功能。我们将使用分子遗传学方法来确定视网膜病变的分子发病机制，并计划使用一种新的药物输送系统来开发用于或难以治疗CMV视网膜炎的玻璃体内治疗方法。首先，我们将确定HIV患者视觉功能障碍的患病率和严重程度。我们假设，HIV患者的这些损害和其他视网膜血管损害的累积效应会导致广泛的视网膜损害，这是视力丧失的原因。我们将确定视网膜结构和功能与生活质量和驾驶模拟等现实世界视觉表现之间的相关性。视网膜损伤将使用新的眼睛跟踪光谱域OCT技术和微视野技术进行评估。多焦电生理学将确定受累最严重的视网膜水平。为了我们的第二个目标，我们将分析尸检眼睛的mRNA，以确定哪些致病途径在受损区域是活跃的。此外，还将采用组织学和形态计量学方法，测定视网膜神经节细胞和神经纤维层的损伤量及其与激活的致病途径的相关性。视神经变性和组织中的细胞凋亡也将被评估。第三个目标是开发一种用于治疗抗药性CMV视网膜炎的超长效给药系统。我们已经确定，某些西多福韦和抗病毒无环核苷膦酸衍生物在体外对HCMV具有很高的活性，即使在病毒对常用的抗CMV化合物产生抗药性的情况下也是如此。我们将使用一种新的脂衍生物方法来结晶这些药物，以允许在眼睛中长期释放和溶解。毒性和药代动力学将得到优化，并在视网膜炎模型中进行测试，作为未来临床试验的先兆。 公共卫生相关性：艾滋病毒患者，即使在高度有效的抗逆转录病毒治疗的时代，也会因视网膜疾病而导致视力丧失。这笔赠款旨在确定视力丧失的性质及其与全身和神经艾滋病毒疾病的关系，并确定非传染性艾滋病毒视网膜病变的分子基础。此外，我们将开发一种新的药物输送系统来治疗抗药性CMV视网膜炎，这是导致HIV患者感染性视网膜炎和视力丧失的最常见原因。

DESCRIPTION (provided by applicant): In the current era of potent antiretroviral therapy, patients with HIV are well known to develop both infectious (typically Cytomegalovirus Retinitis) as well as non-infectious (retinal microvascular occlusions most often seen as cotton wool spots) forms of retinopathy. There are over one million HIV positive individuals in the US and the disease disproportionately affects minorities. At the present time, non-infectious retinopathy is common and we have shown it is a cause of vision loss even in eyes without overt infectious retinitis. There is structural damage to the inner retina in HIV patients and that this correlates with vision loss and dysfunction. Infectious CMV retinitis is still a cause of severe vision loss due to resistant CMV retinitis in patients who are not responding well or who cannot reliably take HAART therapy. We will use novel methods to analyze retinal structure and function in HIV patients. We will use molecular genetic methods to determine the molecular pathogenesis of retinopathy and plan to use a novel drug delivery system to develop intravitreal therapies for or difficult to treat CMV retinitis. First, we will determine the prevalence and severity of visual dysfunction in HIV patients. We hypothesize that the cumulative effect of these lesions and other areas of retinal vessel damage seen in HIV patients cause widespread retinal damage accounting for the vision loss. We will determine the correlates between retinal structure and function and real world vision performance such as quality of life and driving simulation. Retinal damage will be assessed using novel eye tracking spectral domain OCT technology and microperimetric techniques. Multifocal electrophysiology will determine the level of the retina most involved. For our second aim, autopsy eye mRNA will be analyzed to determine which pathogenic pathways are active in damaged areas. In addition, histologic and morphometric methods will be used to determine the amount of retinal ganglion cell and nerve fiber layer damage and it's correlation with activated pathogenic pathways. Optic nerve degeneration and apoptosis in tissue will also be evaluated. The third aim is to develop an ultra long acting drug delivery system for treatment of resistant CMV retinitis. We have determined that certain derivatives of cidofovir and antiviral acyclic nucleoside phosphonates are highly active against HCMV in vitro even in cases of virus resistant to the usually used anti-CMV compounds. We will be using a novel lipid derivitization method to crystallize these drugs to allow prolonged release and dissolution in the eye. Toxicity and pharmacokinetics will be optimized and be tested in models of retinitis as a precursor to future clinical trials. PUBLIC HEALTH RELEVANCE: Patients with HIV disease, even in the era of highly active antiretroviral therapy, develop vision loss from retinal disease. This grant seeks to determine the nature of vision loss and its relationship to systemic and neurological HIV disease and to determine the molecular basis of non infectious HIV retinopathy. In addition, we will be developing a new drug delivery system to treat resistant CMV retinitis which is the most common cause of infectious retinitis and vision loss in HIV patients.