PATHOGENESIS OF HIV ASSOCIATED NEPHROPATHY

HIV相关性神经病变已成为美国终末期肾病（ESRD）项目中的主要流行病。 从20世纪80年代中期偶尔观察到的奇怪现象，HIVAN已成为黑人ESRD的第三大原因。 不幸的是，与许多通过高效抗逆转录病毒疗法（HAART）急剧下降的艾滋病毒感染并发症不同，HIVAN的发病率和流行率继续上升。 对HIVAN持续增加的解释可能反映了HIV-1对黑人城市社区的不成比例的影响。 随着黑人中HIV-1新病例的不成比例的增加和HAART死亡率的下降，处于发展HIVAN风险的患者数量惊人地增加，几乎占艾滋病患者的50%。 要解决这一流行病，需要我们对HIVAN发病机制的理解不断取得进展，但我们已经学到了很多东西。 HIV-1是引起HIVAN和肾小球疾病的主要病原体，并且已经了解。 HIV-1是HIVAN的主要病原体，肾小球和肾小管上皮细胞似乎是靶细胞类型。 最近的研究表明，HIV-1可以在HIVAN患者的肾上皮细胞中检测到。 此外，我们已经确定了一系列上皮替代标记的疾病。 本提案的目的是探索导致发病机制的病毒-宿主相互作用。 其具体目标是首先在体外开发分子标记物，然后使用代表性差异分析（RDA）准确地反映体内发病机制。 这些标记，沿着那些已经被识别的标记，将作为绘制哪些HIV-1基因负责产生HIVAN的读数。 第二个目的是通过体外最小组合HIV-1基因表达来鉴定负责HIVAN发病机制的HIV-1基因产物，所述体外最小组合HIV-1基因表达对于体内HIVAN病理学的发展是必要的，使用研究应该引导我们找到肾脏发病机制的初始途径以及鉴定疾病的下游效应物。结果将定义HIVAN发病机制，提供潜在的治疗靶点，也许最重要的是，提供对黑人所有原因的肾脏疾病的易感性的见解。

HIV associated neuropathy has emerged as a major epidemic in the end stge renal disease (ESRD) program in the United States. From an occasional oddity observed in the mid 1980s, HIVAN has become the third leading cause of ESRD in Blacks. Unfortunately, unlike many of the infectious complications of HIV that have declined dramatically with highly active antiretroviral therapy (HAART), HIVAN continues to increase in both incidence and prevalence. The explanation for the continued increase in HIVAN likely reflects the disproportionate impact that HIV-1 has had on the Black urban community. With the disproportionate increase in new cases of HIV-1 in Blacks and with the decline in mortality from HAART, there has been an astounding increase in the pool of patients at risk for the development of HIVAN to almost 50% of those patients living with AIDS. Continued advances in our understanding of HIVAN pathogenesis are required to address this epidemic, but much has been learned already. HIV-1 is the primary etiologic agent responsible for HIVAN and the renal glomerular and learned already. HIV-1 is the primary etiologic agent responsible for HIVAN and the renal glomerular and tubular epithelium appears to be the targeted cell type. Recent studies have now revealed that HIV-1 can be detected in renal epithelial cells of HIVAN patients. Furthermore, we have identified a series of epithelial surrogate markers for disease. The purpose of this proposal is to explore the viral-host interactions that lead to pathogenesis. The specific aims are first to develop molecular markers in vitro than accurately reflect pathogenesis in vivo using representation difference analysis (RDA). These markers, along with those already identified, will serve as the readout for mapping which HIV-1 genes are responsible for producing HIVAN. The second aim is to identify the HIV-1 gene product(s) responsible for HIVAN pathogenesis by in vitro minimal combinatorial HIV-1 gene expression necessary for the development of HIVAN pathology in vivo using studies should lead us to the initial pathways of renal pathogenesis as well as identify the downstream effectors of disease. Results will define mechanisms of HIVAN pathogenesis, provide potential targets for therapy, and perhaps most importantly, provide insights into the predisposition of Blacks for renal disease of all causes.