PATHOGENESIS OF HIV ASSOCIATED NEPHROPATHY

HIV相关神经病已成为美国终末期肾病(ESRD)计划中的一种主要流行病。从20世纪80年代中期偶尔观察到的奇怪情况来看，HIVAN已成为黑人ESRD的第三大原因。不幸的是，与通过高效抗逆转录病毒疗法(HAART)大幅下降的许多艾滋病毒感染并发症不同，HIVAN的发病率和流行率都在继续增加。艾滋病毒携带率持续上升的原因可能反映了艾滋病毒-1对黑人城市社区的不成比例的影响。随着黑人HIV-1新病例的不成比例增加和HAART死亡率的下降，HIVAN风险患者池中的HIVAN患者数量惊人地增加到近50%的艾滋病患者。要解决这一流行病，需要在我们对HIVAN发病机制的理解上继续取得进展，但已经学到了很多东西。HIV-1是导致HIVAN和肾小球的主要病原体，已经了解到。HIV-1是导致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，在HIVAN患者的肾上皮细胞中可以检测到HIV-1。此外，我们还确定了一系列疾病的上皮替代标志物。这一建议的目的是探索导致发病机制的病毒与宿主的相互作用。其具体目标是首先在体外开发分子标记，而不是使用代表性差异分析(RDA)准确地反映体内的发病机制。这些标记，连同那些已经识别的标记，将作为读数，用于绘制哪些HIV-1基因负责产生HIVAN。第二个目的是通过体外最低限度的HIV-1基因组合表达来鉴定导致HIV-1致病的基因产物(S)，这是体内HIVAN病理发展所必需的，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因素。研究结果将明确HIVAN的发病机制，为治疗提供潜在的靶点，或许最重要的是，为了解黑人患各种原因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.