PATHOGENESIS OF HIV-ASSOCIATED NEPHROPATHY

HIV相关肾病已成为美国非裔美国人ESRD的第三大原因。 这种戏剧性的变化发生在过去的8年里，从一个存在经常被争论的实体转变为每年影响100多名患者的疾病。 在艾滋病毒流行率高的社区，黑人在艾滋病患者中占很大比例，那里的医生对经济和个人成本是众所周知的。 尽管艾滋病毒/艾滋病流行病在人口方面发生了这些巨大变化，但如果我们能够采取适当的治疗和预防战略，仍然需要了解这一疾病的发病机制。 在防治这一疾病方面取得了重大进展。 我们现在知道HIV-1直接参与疾病过程：在动物模型中表达的病毒基因能够复制人类HIVAN的所有特征，肾上皮细胞似乎是HIV发病机制的主要靶点，最近的数据表明病毒可能进入肾上皮细胞。 在这个PPG中，我们打算通过关注三个关键问题来探索HIVAN的发病机制：1。 HIV的种族偏好的遗传基础是什么？ 2. 什么是致病的病毒因素，和3。 HIV-1和导致HIVAN发展的宿主反应之间的关系是什么？ 我们将使用我们实验室开发和广泛表征的转基因小鼠模型以及人类标本来解决这些问题。项目#1将通过定位克隆方法鉴定可能导致HIVAN严重性或其表型突变的候选基因。 项目#2将探索病毒发病机制，包括肾准种的演变，病毒进入的机制，以及肾上皮细胞支持的病毒生命周期中的步骤。 项目#3将通过确定哪些病毒基因产物负责启动HIVAN和宿主对感染的反应来探索病毒-宿主相互作用，使用代表性差异分析来识别候选途径。 核心提供基本的支持功能。核心A将为项目编制补助金提供行政支助。 核心B将提供动物育种支持和肾脏疾病的病理评估，以及人类样本的中央储存库和患有肾脏疾病的HIV-1感染患者的临床数据库。 储存库将包括肾活检和主要病毒分离株。

HIV-associated nephropathy has emerged as the third leading cause of ESRD in African Americans in the United States. This dramatic change has occurred within the past 8 years moving from an entity whose existence was often debated, to a disease affecting over 100 patients per year. The financial and personal costs are well known to physicians in high HIV prevalence communities and where Blacks account for significant percentage of the AIDS patients. Despite these dramatic demographic changes in the HIVAN epidemic, a great deal still needs to be learned about the pathogenesis of this disease if we are able to adopt appropriate treatment and prevention strategies. Significant progress has been made to address this disease. We now know that HIV-1 is directly involved in the disease process: viral genes expressed in an animal model are capable of reproducing all features of HIVAN in man, renal epithelial cells appear to be a major target for HIV pathogenesis, and recent data suggest viral entry into renal epithelial cells is likely. In this PPG, we intend to explore the pathogenesis of HIVAN by focusing on three key questions: 1. What is the genetic basis for racial predilection for HIVAN? 2. What are the viral factors responsible for pathogenesis, and 3. What is the relationship between HIV-1 and the host response that leads to the development of HIVAN? Using both the transgenic mouse model developed and extensively characterized in our laboratory as well as human specimens, we will address these questions. Project #1 will identify candidate genes by positional cloning methods that may be responsible for enhancing the severity of HIVAN or its phenotypic penetrance. Project #2 will explore mechanisms of viral pathogenesis including the evolution of renal quasispecies, the mechanisms of viral entry, and the steps in the viral life cycle supported by the renal epithelia. Project #3 will explore viral-host interactions by determining which viral gene product(s) are responsible for initiating HIVAN and the host response to infection using representational difference analysis to identify candidate pathways. The cores provide essential support functions. Core A will provide the administrative support for the PPG. Core B will provide animal breeding support and pathological assessment of renal disease as well as a central repository for human samples and clinical database for HIV-1 infected patients with renal disease. The repository will include renal biopsy and primary viral isolates.