Studies of Retinopathy of AIDS in the HAART Era

描述（由申请人提供）：在目前强效抗逆转录病毒治疗的时代，众所周知，HIV患者会发展感染性（典型的巨细胞病毒性视网膜炎）和非感染性（视网膜微血管闭塞最常被视为棉絮斑）形式的视网膜病变。美国有100多万艾滋病毒感染者，这种疾病对少数民族的影响尤为严重。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，它也是视力丧失的原因。HIV患者的内视网膜存在结构性损伤，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严重视力丧失的一个原因，这是由于耐药巨细胞病毒视网膜炎在反应不佳或不能可靠地接受HAART治疗的患者中引起的。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传递系统来开发治疗或难以治疗巨细胞病毒性视网膜炎的玻璃体内疗法。首先，我们将确定艾滋病毒患者视力功能障碍的患病率和严重程度。我们假设这些病变和其他区域的视网膜血管损伤的累积效应在HIV患者中看到导致广泛的视网膜损伤导致视力丧失。我们将确定视网膜结构和功能与现实世界的视觉表现之间的相关性，如生活质量和驾驶模拟。视网膜损伤将使用新的眼动追踪光谱域OCT技术和显微测量技术进行评估。多焦点电生理将决定视网膜的最受影响的水平。对于我们的第二个目标，解剖眼mRNA将被分析，以确定哪些致病途径是活跃的受损区域。此外，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损伤的数量及其与激活的致病途径的关系。视神经退行性变和组织凋亡也将被评估。第三个目标是开发一种治疗耐药巨细胞病毒视网膜炎的超长效药物输送系统。我们已经确定，西多福韦的某些衍生物和抗病毒的无环核苷膦酸盐在体外对HCMV具有高度活性，即使在病毒对通常使用的抗cmv化合物具有抗性的情况下也是如此。我们将使用一种新的脂质衍生物化方法来结晶这些药物，以延长药物在眼睛中的释放和溶解时间。毒性和药代动力学将在视网膜炎模型中进行优化和测试，作为未来临床试验的先驱。

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.