Studies of Retinopathy of AIDS in the HAART Era

摘要 在目前有效的抗逆转录病毒治疗的时代，众所周知，艾滋病病毒感染者会同时发展这两种疾病。 感染性（通常是巨细胞病毒视网膜炎）以及非感染性（视网膜微血管 闭塞最常被视为棉絮斑）形式的视网膜病变。有超过一百万 美国的艾滋病毒阳性者和这种疾病不成比例地影响少数民族。在 目前，非感染性视网膜病变是常见的，我们已经表明，这是一个原因，视力丧失 即使在没有明显感染性视网膜炎的眼睛中也是如此。在HIV中，视网膜内层有结构性损伤， 这与视力丧失和功能障碍有关。感染性CMV视网膜炎仍然是一种 在反应不佳的患者中，由于耐药CMV视网膜炎导致的严重视力丧失的原因，或 无法可靠地接受HAART治疗的患者。我们将使用新的方法来分析视网膜结构， 在艾滋病患者中发挥作用。我们将使用分子遗传学方法来确定 视网膜病变的发病机制，并计划使用一种新的药物输送系统， 治疗CMV视网膜炎或难以治疗CMV视网膜炎。首先，我们将确定 艾滋病患者的视力障碍。我们假设这些病变的累积效应， 在HIV患者中看到的视网膜血管损伤的其他区域引起广泛的视网膜损伤 导致视力下降我们将确定视网膜结构和功能之间的相关性 以及生活质量和驾驶模拟等真实的世界视觉性能。视网膜损伤会 使用新型眼动跟踪光谱域OCT技术和微周边测量进行评估 技术.多焦电生理学将确定最受影响的视网膜水平。为我们 第二个目标是分析尸体眼的mRNA，以确定哪些致病途径是活跃的 在受损地区。此外，将使用组织学和形态学方法来确定 视网膜神经节细胞和神经纤维层损伤的数量及其与激活的相关性 致病途径还将评价组织中的视神经变性和细胞凋亡。的 第三个目标是开发用于治疗耐药CMV的超长效药物递送系统 视网膜炎我们已经确定西多福韦和抗病毒无环核苷的某些衍生物 膦酸盐在体外对HCMV具有高度活性，即使在病毒对通常的 使用抗CMV化合物。我们将使用一种新的脂质衍生化方法来结晶这些 药物，以允许在眼睛中延长释放和溶解。毒性和药代动力学将 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驱。

ABSTRACT 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.