Novel mechanisms of antiretroviral protection against HIV-related kidney diseases

抗逆转录病毒保护艾滋病毒相关肾脏疾病的新机制

基本信息

批准号：
9320762
负责人：
MICHAEL J ROSS
金额：
$ 37.58万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9320762
关键词：
AIDS-Associated Nephropathy AIDS/HIV problem Address Animal Model Anti-Retroviral Agents Cells Cessation of life Chronic Kidney Failure Clinical Research Data Development Diabetes Mellitus Diabetic Nephropathy Disease End stage renal failure Epithelial Epithelial Cells FVB Mouse Gene Expression Genetic Goals HIV HIV Infections HIV Protease Inhibitors HIV-1 HIV-1 protease In Vitro Incidence Inflammatory Response Injury Kidney Kidney Diseases Mediating Mediator of activation protein Molecular Mus Nephrotic Syndrome Outcome Pathogenesis Patients Peptide Hydrolases Persons Pharmaceutical Preparations Phenotype Population Prevalence Protease Inhibitor Protein Inhibition Proviruses Public Health Publishing RNA-Directed DNA Polymerase Research Reverse Transcriptase Inhibitors Risk Role Series Severities Steroids Stimulus Subfamily lentivirinae Testing Transgenic Model Transgenic Organisms Tubular formation Viral Virus Replication Vulnerable Populations Wit Work adenylate kinase antiretroviral therapy cellular targeting diabetic env Genes improved in vivo in vivo Model innovation insight kidney cell kidney epithelial cell mortality mouse model novel novel strategies podocyte pol genes prevent public health relevance response to injury success

项目摘要

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.¿

描述：肾脏疾病是艾滋病毒感染者和与艾滋病毒相关的肾病（Hivan）的第四个领先的贡献者，是该人群中终阶段肾脏疾病的最常见原因。此外，艾滋病毒感染者的糖尿病和艾滋病毒感染的风险增加，增加了糖尿病患者进行性慢性肾脏病（CKD）的风险。抗逆转录病毒疗法（ART）通常在患有HIVAN风险的患者中有效，但是保护肾脏的机制尚不清楚，因为动物模型表明HIV发病机理不需要病毒复制。尚不清楚ART对艾滋病毒感染的非肝癌疾病（如糖尿病肾病）的肾脏结局的影响。最近发表的一项临床研究的结果表明，HIV蛋白酶抑制剂可能在患有CKD的HIV阴性患者中有效，表明这些药物可以通过独立于对病毒复制的影响来保护肾脏。我们的长期目标是了解艾滋病毒感染使患者易于促进新型策略以预防和治疗这种脆弱人群的肾脏疾病的机制。该提案的目的是确定艺术可以防止与HIV相关的肾脏疾病的新型机制。我们的中心假设是，通过独立于抑制HIV复制的机制，ART可以保护肾脏免受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的数据的支持，其他人则证明：1）VPR和/或NEF的肾上皮表达足以在没有病毒复制的情况下诱导Hivan； 2）ART可以改善患者的Hivan，而不会降低肾上皮HIV表达； 3）HIV蛋白抑制剂在治疗非HIV相关肾脏疾病方面具有有效性； 4）初步数据表明，HIV蛋白抑制剂可保护肾脏免受HIV基因表达和非HIV肾脏损伤的有害作用。拟议工作的理由是，更好地了解艺术如何保护与HIV相关的肾脏疾病将有助于预防和治疗肾脏疾病的新策略。我们将在两个具体目标中检验我们的假设，并解决至关重要的问题。在我们的第一个特定目标中，我们将使用HIV - 转基因鼠模型的肾脏疾病模型来阐明ART在预防和治疗Hivan和糖尿病性肾小球损伤方面的HIV独立作用。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保护肾细胞免受HIV的有害影响的分子机制，而不是对HIV对HIV复制的影响的有害作用，包括新的研究，以解读AMP-激酶在介导蛋白酶抑制剂的肾脏保护作用中的作用。我们提出了创新的方法，以发现艺术保护肾脏免受艾滋病毒和其他伤害的新型机制。这些结果将产生积极的影响，因为它们将提供新的见解，以提高我们在艾滋病毒/艾滋病患者中预防和治疗肾脏疾病的能力。