Studies of Retinopathy of AIDS in the HAART Era

摘要 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(典型的巨细胞病毒性视网膜炎)以及非感染性(视网膜微血管 阻塞，最常见的是棉花斑点)形式的视网膜病变。有100多万个 在美国，艾滋病毒阳性者和这种疾病对少数族裔的影响不成比例。在 目前，非感染性视网膜病变很常见，我们已经证明它是导致视力丧失的原因之一。 即使眼睛没有明显的感染性视网膜炎。HIV病毒对视网膜内部有结构性损伤 这与视力丧失和功能障碍有关。传染性CMV视网膜炎仍然是一种 由于抗药性巨细胞病毒视网膜炎导致的严重视力丧失的原因是反应不佳或 不能可靠地接受HAART治疗的人。我们将使用新的方法来分析视网膜结构和 在HIV患者中的功能。我们将使用分子遗传学方法来确定分子 视网膜病变的发病机制和计划使用一种新的药物输送系统来发展玻璃体内 治疗或难以治疗巨细胞病毒性视网膜炎。首先，我们将确定该病的患病率和严重性 HIV患者的视觉功能障碍。我们假设这些损伤的累积效应和 HIV患者视网膜血管损伤的其他区域会导致广泛的视网膜损伤 造成视力丧失的原因。我们将确定视网膜结构和功能之间的相关性 以及真实世界的视觉表现，如生活质量和驾驶模拟。视网膜损伤会 使用新的眼球跟踪光谱域OCT技术和微视野进行评估 技巧。多焦电生理学将确定受累最严重的视网膜水平。为我们的 第二个目的，将分析尸检眼睛的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计量学方法来确定 视网膜神经节细胞和神经纤维层损伤量及其与激活的关系 致病途径。视神经变性和组织中的细胞凋亡也将被评估。这个 第三个目标是开发一种治疗耐药巨细胞病毒的超长效药物输送系统 视网膜炎。我们已经确定了西多福韦和抗病毒无环核苷的某些衍生物 磷酸盐在体外对人巨细胞病毒具有很高的活性，即使在病毒对通常 使用了抗CMV的化合物。我们将使用一种新的脂衍生物方法来结晶这些 能够在眼睛中长时间释放和溶解的药物。毒性和药代动力学 经过优化，并在视网膜炎模型中进行测试，作为未来临床试验的先兆。

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.