PATHOGENESIS OF HIV ASSOCIATED NEPHROPATHY

HIV相关的神经病变已成为美国终末期肾病（ESRD）项目的主要流行病。从20世纪80年代中期偶尔观察到的奇怪现象，hiv已经成为黑人ESRD的第三大原因。不幸的是，与通过高效抗逆转录病毒治疗（HAART）已显著减少的许多艾滋病毒感染并发症不同，艾滋病毒感染在发病率和流行率方面都在继续增加。对hiv持续增长的解释可能反映了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，艾滋病毒感染风险患者的数量惊人地增加，几乎占艾滋病患者的50%。要解决这一流行病，我们需要继续增进对艾滋病毒发病机制的了解，但我们已经了解了很多。HIV-1是导致hiv和肾小球的主要病因，这一点我们已经知道了。HIV-1是HIVAN的主要病原，肾小球和肾小管上皮似乎是目标细胞类型。最近的研究表明，HIV-1可以在hiv患者的肾上皮细胞中检测到。此外，我们已经确定了一系列疾病的上皮替代标志物。本提案的目的是探索导致发病机制的病毒-宿主相互作用。具体目标是首先开发体外分子标记，然后使用表征差异分析（RDA）准确反映体内发病机制。这些标记，连同那些已经确定的标记，将作为绘制哪些HIV-1基因负责产生HIV-1的读数。第二个目标是通过体外最低限度的组合HIV-1基因表达来鉴定负责HIV-1发病机制的基因产物，这是体内发展HIV-1病理所必需的，使用研究将引导我们找到肾脏发病的初始途径以及确定疾病的下游效应物。研究结果将明确hiv的发病机制，提供潜在的治疗靶点，也许最重要的是，为黑人对各种原因的肾脏疾病的易感性提供见解。

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.