Novel mechanisms of antiretroviral protection against HIV-related kidney diseases

 描述：肾脏疾病是导致HIV感染者死亡的第四大原因，而HIV相关肾病(HIVAN)是导致该人群终末期肾脏疾病的最常见原因。此外，艾滋病毒感染者患糖尿病的风险增加，艾滋病毒感染增加了糖尿病患者患进行性慢性肾脏病的风险。抗逆转录病毒疗法(ART)对有HIVAN风险的患者通常有效，但其保护肾脏的机制尚不清楚，因为动物模型表明HIVAN的发病不需要病毒复制。ART对患有非HIVAN肾脏疾病(如糖尿病肾病)的HIV感染患者肾脏结局的影响尚不清楚。最近发表的一项临床研究结果表明，HIV蛋白酶抑制剂可能对HIV阴性的CKD患者有效，表明这些药物可能通过独立于病毒复制影响的机制保护肾脏。我们的长期目标是了解HIV感染使患者易患CKD的机制，以促进在这一脆弱人群中预防和治疗肾脏疾病的新策略的开发。这项建议的目的是确定ART可以防止HIV相关肾脏疾病进展的新机制。我们的中心假设是，ART可能通过独立于抑制HIV复制的机制来保护肾脏免受HIV诱导的上皮损伤和炎症反应。我们的假设得到了我们实验室和其他实验室数据的支持，这些数据表明：1)在没有病毒复制的情况下，VPR和/或Nef的表达足以引发HIVAN；2)ART可以改善患者的HIVAN，而不会降低肾脏上皮细胞HIV的表达；3)HIV蛋白酶抑制剂在治疗非HIV相关肾脏疾病方面具有疗效；4)初步数据表明，HIV蛋白酶抑制剂可以保护肾脏免受HIV基因表达和非HIV肾脏损伤的有害影响。这项拟议工作的基本原理是，更好地了解抗逆转录病毒疗法如何预防艾滋病毒相关的肾脏疾病，将使预防和治疗肾脏疾病的新战略成为可能。我们将测试我们的假设，并在两个具体目标上解决至关重要的问题。在我们的第一个具体目标中，我们将使用HIV转基因小鼠肾脏疾病模型来阐明ART在预防和治疗HIVAN和糖尿病肾小球损伤中对HIV非依赖的作用。在我们的第二个特定目标中，我们将进行一系列研究，以确定ART保护肾脏细胞免受HIV有害影响的分子机制，而不是对HIV复制的影响，包括破译AMP-K在介导蛋白酶抑制剂的肾脏保护效应中的作用的新研究。我们提出了创新的方法来发现ART保护肾脏免受艾滋病毒和其他侮辱的新机制。这些结果将产生积极影响，因为它们将提供新的见解，提高我们预防和治疗艾滋病毒/艾滋病患者肾脏疾病的能力。

 DESCRIPTION: Kidney disease is the fourth-leading contributor to death in HIV-infected persons and HIV-associated nephropathy (HIVAN) is the most common cause of end stage renal disease in this population. Moreover, HIV-infected persons are at increased risk of developing diabetes mellitus and HIV infection increases the risk of progressive chronic kidney disease (CKD) in patients with diabetes. Antiretroviral therapy (ART) is often effective in treatin patients at risk for HIVAN but the mechanism by which it protects the kidney is unclear since animal models suggest that viral replication is not required for HIVAN pathogenesis. The effects of ART upon renal outcomes in HIV infected patients with non-HIVAN kidney diseases such as diabetic nephropathy are not clear. The results of a recently published clinical study suggest that HIV protease inhibitors may be efficacious in HIV negative patients with CKD, indicating that these medications may protect the kidney via mechanisms that are independent of effects on viral replication. Our long-term goal is to understand the mechanisms by which HIV infection predisposes patients to CKD to facilitate development of novel strategies to prevent and treat kidney disease in this vulnerable population. The objective of this proposal is to identify novel mechanisms by which ART may prevent the progression HIV-associated kidney diseases. Our central hypothesis is that ART may protect the kidney against HIV-induced epithelial injury and inflammatory response via mechanisms that are independent of suppression of HIV replication. Our hypothesis is supported by data from our lab and others demonstrating that: 1) renal epithelial expression of Vpr and/or Nef are sufficient to induce HIVAN in the absence of viral replication; 2) ART can ameliorate HIVAN in patients without decreasing renal epithelial HIV expression; 3) HIV protease inhibitors have efficacy in the treatment of non- HIV related kidney disease; 4) preliminary data suggesting that HIV protease inhibitors protect the kidney from deleterious effects of HIV gene expression and non-HIV renal injury. The rationale for the proposed work is that better understanding how ART protects against HIV-related kidney diseases will enable new strategies to prevent and treat kidney disease. We will test our hypothesis and address critically important questions in two specific aims. In our first specific aim, we will use HIV-transgenic murine models of kidney disease to elucidate the HIV-independent effects of ART in preventing and treating HIVAN and diabetic glomerular injury. In our second specific aim, we will perform a series of studies to determine the molecular mechanisms by which ART protects kidney cells from the deleterious effects of HIV independent of effects on HIV replication, including novel studies to decipher the role of AMP-kinase in mediating the renoprotective effects of protease inhibitors. We propose innovative approaches to discover novel mechanisms by which ART protects the kidney from HIV and other insults. These results will have a positive impact because they will provide new insights that will improve our ability to prevent and treat kidney disease in persons living with HIV/AIDS.¿