Role of ctyokines and APOL-1 in the pathogenesis of childhood HIV associated neph

hiv相关肾病（HIVAN）是一种肾脏疾病，几乎只发生在非洲血统的人群中。它是由HIV-1感染和损伤足细胞和肾小管上皮细胞（RTEc）直接引起的。虽然体内HIV-1感染肾上皮细胞的机制尚未阐明，但内源性宿主因子被认为在这一过程中起着至关重要的作用。此外，APOL1基因（G1/G2）的变异最近被确定为成人发生hiv的主要风险。确定APOL1变异体促进HIVAN发展的机制可以深入了解HIVAN发病机制的潜在机制。最近，我们发现肿瘤坏死因子α (TNF-a)是促进HIVAN患儿足细胞感染的关键宿主因子。在感染HIV-1的情况下，TNF-a也会增加ApoL-1的表达，ApoL-1是一种在生理水平上调节自噬的蛋白质。我们假设TNF-a是通过促进肾上皮细胞感染和增加apol -1表达而在儿童hiv发病机制中起关键作用的宿主因子。在HIV-1感染的足细胞中，APOL1风险变异体的过度表达，使足细胞死亡增加，引发肾上皮损伤，从而在HIV-1的发展中沉淀。这一假设将在三个方面得到验证。在目标1中，我们将定义TNF-a如何影响病毒进入和

DESCRIPTION: HIV-associated nephropathy (HIVAN) is a renal disease almost exclusively seen in people of African ancestry. It is caused directly by the infection and injury of podocytes and renal tubular epithelial cells (RTEc) by HIV-1. While the mechanism for renal epithelial cell infection by HIV-1 in vivo has not been elucidated, endogenous host factors are believed to play a crucial role in this process. Additionally variants in the APOL1 gene (G1/G2) were recently identified as a major risk for developing HIVAN in adults. Identifying the mechanism by which APOL1 variants precipitate the development of HIVAN can provide insights into the underlying mechanism involved in the pathogenesis of HIVAN. Recently we identified tumor necrosis factor alpha (TNF-a) as a critical host factor that facilitates the infection of podocytes cultured from children with HIVAN. TNF-a, in presence of infectious HIV-1, also increases the expression of ApoL-1, a protein that at physiological levels regulates autophagy. We hypothesize that TNF-a is the host factor that plays a critical role in the pathogenesis of childhood HIVAN by facilitatin infection of renal epithelial cells and increasing ApoL-1expression. In HIV-1 infected podocytes, over expression of the APOL1 risk variants, tip the balance to increased podocyte death triggering renal epithelial injury, which precipitates in the development of HIVAN. This hypothesis will be tested in three aims. In aim 1, we will define how TNF-a affects viral entry and infection of podocytes and RTEc cultured from children with HIVAN, and identify the TNF-a domain involved in this process. In aim 2, we will determine how ApoL-1 modulates the survival of infected podocytes in culture by interacting with TNF-a, viral proteins, and endocytic or autophagic pathways for viral entry and degradation. In aim 3, we will define how APOL1 and TNF-a affect the renal outcome of young wild type and HIV-Tg26 mice, and validate relevant clinical findings in renal sections, cells, and urine samples collected from children with HIVAN. These experiments will generate highly relevant clinical information to understand how children develop HIVAN.