PATHOGENESIS OF HIV-ASSOCIATED NEPHROPATHY

hiv相关肾病已成为美国非裔美国人ESRD的第三大病因。这一巨大变化是在过去8年里发生的，从一个存在争议的实体，变成了每年影响100多名患者的疾病。在艾滋病毒高流行社区和黑人占艾滋病患者很大比例的社区，医生们都知道这种财务和个人成本。尽管艾滋病毒流行的人口结构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，我们仍然需要了解这种疾病的发病机制。在防治这一疾病方面已取得重大进展。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在人体内复制HIV的所有特征，肾上皮细胞似乎是HIV发病的主要靶点，最近的数据表明病毒可能进入肾上皮细胞。在这个PPG中，我们打算从三个关键问题来探讨hiv的发病机制：1。hiv的种族偏好的遗传基础是什么？2. 2 .致病的病毒因子有哪些？HIV-1与导致hiv发展的宿主反应之间的关系是什么？利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，我们将解决这些问题。项目#1将通过定位克隆方法确定候选基因，这些基因可能负责提高hiv的严重程度或其表型外显率。项目#2将探索病毒的发病机制，包括肾脏准种的进化，病毒进入的机制，以及由肾上皮支持的病毒生命周期的步骤。项目#3将通过确定哪些病毒基因产物负责启动hiv和宿主对感染的反应来探索病毒与宿主的相互作用，使用代表性差异分析来确定候选途径。核心提供基本的支持功能。核心A将为PPG提供行政支持。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存储库和艾滋病毒-1感染肾脏疾病患者的临床数据库。该库将包括肾活检和原代病毒分离物。

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.