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

• 批准号: 8927621
• 负责人: MICHAEL J ROSS
• 金额: $ 38.14万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/8927621
• 关键词: AIDS-Associated Nephropathy; AIDS/HIV problem; Address; Animal Model; Anti-Retroviral Agents; Breeding; 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; Gagging; Gene Expression; Genetic; Goals; HIV; HIV Infections; HIV Protease Inhibitors; HIV-1; In Vitro; Incidence; Inflammatory Response; Injury; Kidney; Kidney Diseases; Life; Mediating; Mediator of activation protein; Modeling; 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; Vulnerable Populations; Work; adenylate kinase; antiretroviral therapy; cellular targeting; diabetic; env Genes; improved; in vivo; in vivo Model; innovation; insight; kidney cell; kidney epithelial cell; mortality; novel; novel strategies; podocyte; pol genes; prevent; public health relevance; response to injury; success

 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死亡的第四大原因，艾滋病毒相关肾病（HIVAN）是该人群中终末期肾病的最常见原因，此外，艾滋病毒感染者患艾滋病的风险增加。糖尿病和 HIV 感染会增加糖尿病患者罹患进行性慢性肾病 (CKD) 的风险。抗逆转录病毒疗法 (ART) 通常对治疗有 HIVAN 风险的患者有效，但其治疗机制却不尽相同。由于动物模型表明 HIVAN 发病机制不需要病毒复制，因此 ART 对患有非 HIVAN 肾病（例如糖尿病肾病）的 HIV 感染患者的肾脏结局的影响尚不清楚。临床研究表明，HIV 蛋白酶抑制剂可能对 HIV 阴性 CKD 患者有效，这表明这些药物可能通过独立于病毒复制影响的机制来保护肾脏。我们的长期目标是了解 HIV 的机制。感染使患者易患 CKD，以促进制定预防和治疗这一弱势群体肾脏疾病的新策略。该提案的目的是确定 ART 可以预防 HIV 相关肾脏疾病进展的新机制。 ART 可以通过独立于 HIV 复制抑制的机制保护肾脏免受 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人的数据的支持，这些数据表明：1）Vpr 和/或 Nef 的肾上皮表达。是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，而不降低肾上皮 HIV 表达；3) HIV 蛋白酶抑制剂对治疗非 HIV 相关的肾脏疾病有效； HIV 蛋白酶抑制剂可保护肾脏免受 HIV 基因表达和非 HIV 肾损伤的有害影响。拟议工作的基本原理是，更好地了解 ART 如何预防 HIV 相关的肾脏疾病将有助于制定新的预防和治疗策略。我们将测试我们的假设并解决两个具体目标中的至关重要的问题。在我们的第一个具体目标中，我们将使用 HIV 转基因小鼠肾病模型来阐明 ART 在预防和治疗 HIVAN 方面的独立于 HIV 的作用。在我们的第二个具体目标中，我们将进行一系列研究，以确定 ART 保护肾细胞免受 HIV 有害影响的分子机制，而与 HIV 复制的影响无关，包括破译其作用的新研究。 AMP 激酶介导蛋白酶抑制剂的肾脏保护作用，我们提出了创新方法来发现 ART 保护肾脏免受艾滋病毒和其他损伤的新机制。这些结果将产生积极的影响，因为它们将提供新的见解，从而提高我们的能力。预防和治疗艾滋病毒/艾滋病患者的肾脏疾病。¿