Role of cytokines and APOL-1 in the pathogenesis of childhood HIV associated nephrology

细胞因子和 APOL-1 在儿童 HIV 相关肾病发病机制中的作用

• 批准号: 9884756
• 负责人: PATRICIO E RAY
• 金额: $ 36.34万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884756
• 关键词: AIDS-Associated Nephropathy; APOL1 gene; Adult; Affect; African; Archives; Autophagocytosis; Autopsy; Biopsy; CRISPR/Cas technology; Cell Line; Cells; Cessation of life; Child; Childhood; Chronic Kidney Failure; Cultured Cells; Development; Drosophila genus; Dynamin; Endocytosis; Epithelial Cells; Equilibrium; Event; Genes; Genotype; Grant; HIV; HIV Infections; HIV-1; Human; Impairment; Infection; Inflammatory; Inflammatory Infiltrate; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Lead; Modeling; Mononuclear; Mus; Names; Nephrology; Pathogenesis; Pathway interactions; Patients; Physiological; Plasma; Play; Prevalence; Process; Risk; Role; Signal Pathway; Structure; TNF gene; Technology; Testing; Tissues; Transcript; Tubular formation; Tumor Necrosis Factor Receptor; Urine; Vacuole; Viral Load result; Workload; antiretroviral therapy; cytokine; experimental study; fly; high risk; in vivo; inhibitor/antagonist; insight; novel therapeutics; particle; podocyte; prevent; renal epithelium; risk variant; small hairpin RNA; synergism; trafficking; transmission process; young adult

SUMMARY HIV-associated nephropathy (HIVAN) is a renal disease caused by the infection of renal epithelial cells (REc) that is seen more frequently in people of African ancestry who carry two APOL1 risk alleles (APOL1-RA) named G1 or G2. The study of HIVAN provides a unique opportunity to define how contacts between HIV+ inflammatory cells and REc may contribute to establish a kidney HIV-1 reservoir, and to determine how APOL1 interact with HIV-1 to precipitate HIVAN in people of African ancestry. In the first cycle of the grant, we have demonstrated that transmembrane TNF-α (tm-TNF-α) facilitates the infection of podocytes and REc cultured from children with HIVAN, and increases the expression of APOL1 in synergy with HIV-1. We also found that tm-TNF-α and APO1 interact to modulate common pathways involved in endocytosis, HIV-1 trafficking, and degradation in REc. Thus, we hypothesize that tm-TNF-α plays a critical role in the pathogenesis of childhood HIVAN by facilitating the infection of REc through cell-to-cell contacts with mononuclear cells, and by increasing the activity of APOL1-RA in these cells. In HIV+ podocytes, these changes tip their homeostatic balance, impairing key endocytic and autophagic pathways that affect their structure, function, and survival. In turn, these events precipitate HIVAN in children and adults. This hypothesis will be tested in three aims. In aim 1, we will determine how tm-TNF-α modulates the transfer of HIV-1 from mononuclear cells to REc cultured from HIV+ children, and elucidate the mechanisms involved. In aim 2 we will define how tm-TNF−α and APOL1-RA interact in vivo to modulate relevant endocytic and autophagy pathways that are essential for the normal function of Drosophila nephrocytes (the fly equivalent of human podocytes) and for the traffic of HIV-1 particles in podocytes. In aim 3, we will determine how APOL1-RA modulate the infection of podocytes cultured from HIV+ children, and define the risk of children carrying two APOL1 RA to develop HIVAN. In summary, these experiments will elucidate how REc are infected with HIV-1, and interact with renal infiltrating inflammatory cells and the APOL1-RA to establish a renal HIV-reservoir and induce chronic kidney diseases.

摘要 人类免疫缺陷病毒相关性肾病(HIVAN)是一种由肾上皮细胞感染引起的肾脏疾病。 这在携带两个APOL1风险等位基因(APOL1-RA)的非洲血统的人中更常见 命名为G1或G2。对HIVAN的研究提供了一个独特的机会来定义HIV+之间的接触 炎症细胞和Rec可能有助于建立肾脏HIV-1储存库，并确定APOL1如何 与艾滋病毒-1相互作用，在非洲血统的人中沉淀艾滋病毒。在赠款的第一个周期中，我们有 跨膜型肿瘤坏死因子-α(tm-肿瘤坏死因子-α)促进足细胞和培养的REC感染 并与HIV-1协同作用增加APOL1的表达。我们还发现， TM-肿瘤坏死因子-α和载脂蛋白1相互作用，调节共同的途径，涉及内吞作用，艾滋病毒-1运输，和 记录中的退化。因此，我们假设tm-ntf-α在儿童发病机制中起关键作用。 HIVAN通过与单个核细胞的细胞间接触促进Rec的感染，并通过 增加这些细胞的APOL1-RA活性。在HIV+足细胞中，这些变化改变了它们的动态平衡 平衡，损害关键的内吞和自噬途径，影响其结构、功能和生存。在……里面 反过来，这些事件会在儿童和成人中引发艾滋病毒。这一假设将在三个目标上得到检验。在……里面 目的1，我们将确定tm-肿瘤坏死因子-α如何调节HIV-1从单个核细胞向REC的转移 从HIV阳性的儿童身上培养，并阐明其中的机制。在目标2中，我们将定义tm-肿瘤坏死因子−α如何 和APOL1-RA在体内相互作用，调节相关的内吞和自噬途径，这些途径对 果蝇肾细胞(相当于人足细胞的果蝇)的正常功能 足细胞中的HIV-1颗粒。在目标3中，我们将确定APOL1-RA是如何调节足细胞感染的 来自HIV+儿童的培养，并确定儿童携带两个APOL1 RA发展为HIVAN的风险。在……里面 总结，这些实验将阐明Rec如何感染HIV-1，并与肾脏浸润性疾病相互作用 炎症细胞和APOL1-RA建立肾脏艾滋病毒储存库，并诱导慢性肾脏疾病。