Studies of Retinopathy of AIDS in the HAART Era

描述：（申请人提供）在高活性抗逆转录病毒时代 在HAART治疗后，HIV感染的视网膜表现发生了变化。的 这项资助的首要目标是应用最新的分子生物学， 免疫学、临床研究和药物开发技术， 了解这些表现。UCSD HIV研究环境包括 与几个主要的NIH资助团体合作， 这些目标。CMV视网膜炎仍然是一个问题，特别是在没有 获得HAART或HAART失败的人;特别是代表性不足的少数群体 社区我们计划确定哪些个体有免疫风险， CMV视网膜炎及研究CMV视网膜炎免疫恢复的新表现 通过分析这些患者的眼液和组织， 使用分子方法检测细胞因子和CMV复制的存在。此外 我们将评估抗CMV治疗在治疗免疫性 在UCSD IRB批准的随机临床试验中恢复葡萄膜炎。的 非感染性视网膜病变的艾滋病毒，视网膜棉絮斑和微血管 疾病，我们仍然知之甚少。我们希望确定 病理学和临床相关性以及HAART治疗与此的关系 这种疾病可引起局灶性视网膜破坏， 视觉功能障碍。我们将通过分析尸检组织 从NIH资助的加州神经艾滋病组织网络和我们的 自己的患者群体。此外，我们还将研究这一关系， 视网膜病变与神经认知功能障碍的关系 共同参加了NIMH资助的UCSD艾滋病毒神经行为研究中心。 我们的第三个目标是开发一种新型的长效玻璃体内给药系统 该系统可以在临床上作为小注射剂施用。这是 重要的是，因为耐药CMV视网膜炎仍然是一个问题， HAART治疗失败。目前，抗CMV治疗， 特别是玻璃体内治疗，没有被积极追求， 制药公司。我们将合成和鉴定新的抗病毒药物 脂质结合药物是更昔洛韦和膦甲酸的衍生物。的 这些化合物的抗CMV活性将在体外和长效 将生产脂质衍生物，然后在实验室动物中进行测试。的 将确定玻璃体内治疗指数和药效学， 在视网膜炎模型中研究功效。这将使开发成本低 可注射药物递送系统，其将允许治疗耐药的 视网膜炎，每3个月或更长的时间间隔，没有额外的费用， 手术室里的手术风险。

DESCRIPTION: (provided by applicant) In the era of highly active antiretroviral therapy (HAART), the retinal manifestations of HIV infections have changed. The overarching goal of this grant is to apply the latest molecular biological, immunological, clinical study and drug development techniques to better understand these manifestations. The UCSD HIV study environment includes collaborations with several major NIH funded groups allowing fulfillment of these goals. CMV retinitis remains a problem, particularly in patients without access to or who fail HAART; especially the under represented minority community. We plan to determine which individuals are at immunological risk for CMV retinitis and to study a new manifestation of CMV retinitis immune recovery uveitis by analyzing ocular fluids and tissue from such patients for the presence of cytokines and CMV replication using molecular methods. In addition we will evaluate the role of anti-CMV therapy in the treatment of immune recovery uveitis in a UCSD IRB-approved randomized clinical trial. The non-infectious retinopathy of HIV, retinal cotton wool spots and microvascular disease, is still poorly understood. We wish to determine the molecular pathology and clinical correlates and relationship of HAART therapy to this disorder which is reponsible for focal retinal destruction and probably for visual dysfunction as well. We will do this by analyzing autopsy tissue obtained from the NIH funded California NeuroAIDS Tissue Network and from our own patient population. In addition, we will study the relationship of this retinopathy to neurocognitive dysfunction by studying a cohort of patients jointly enrolled in the NIMH funded UCSD HIV neurobehavioral research center. Our third aim is to develop a novel long acting intravitreal drug delivery system that can be administered as a small injection in the clinic. This is important because resistant CMV retinitis is still a problem in patients who have failed HAART therapy. At the current time, anti-CMV therapies, particularly intravitreal therapies, are not being aggressively pursued by pharmaceutical companies. We will synthesize and characterie new antiviral lipid conjugated drugs that are derivatives of ganciclovir and foscarnet. The anti-CMV activity of these compounds will be tested in vitro and long acting lipid derivatives will be produced and then tested in laboratory animals. The intravitreal therapeutic index and pharmacodynamics will be determined and efficacy studied in retinitis models. This will allow development of a low cost injectable drug delivery system that will allow treatment of resistant retinitis at intervals of every 3 months or longer without the added cost and risk of surgery in the operating room.