PROJECT SUMMARY/ABSTRACT Most of the 2.5 million children and adolescents living with HIV-1 (CALWH) worldwide reside in Sub-Saharan Africa. Those who carry two copies of the APOL1 risk alleles (RA) are at higher risk of developing HIV-chronic kidney diseases (HIV-CKD) if they are not treated continuously with modern anti-retroviral therapy (ART) throughout childhood. During the last grant cycle, we followed the outcome of ~ 200 CALWH in the Washington DC area for an average period of 5 years, and found that many developed HIV-CKD despite ART. We also found that children with high plasma and urine levels of the heparin binding cytokine Fibroblast Growth Factor-2 (FGF- 2), were at further risk of developing HIV-CKD, and that FGF-2 increased the renal recruitment and attachment of HIV+ cells in mice. Thus, we hypothesize that FGF-2 release into the circulation accelerates the progression of childhood HIV-CKD, acting in synergy with the APOL1-RA and other HIV proteins, by facilitating the renal recruitment of HIV-infected cells, as well as the infection and/or injury of renal cells despite ART. We further hypothesize that FGF-2 precipitates the detachment of viable podocytes and tubular epithelial cells (REc), and that the phenotype and transcriptome profiles of these cells can be used to distinguish CALWH undergoing HIVAN and/or other progressive HIV-CKD, and to follow their outcome in a non-invasive manner. This hypothesis will be tested in three aims. In aim 1, we will define how FGF-2 and APOL1-RA interact to precipitate HIV-CKDs in CALWH on ART, and define the clinical value of single cell urinary transcriptome profiles to distinguish CALWH undergoing HIVAN and/or other progressive HIV-CKD. In aim 2, we will determine how FGF-2 and APOL1-RA interact to modulate the infection, injury, and/or survival of HIV-infected cells cultured from children with HIV- CKD. In aim 3, we will use two new mouse models of childhood HIV-CKD, to determine how FGF-2 interacts with APOL1-RA and HIV-Nef to precipitate the detachment of podocytes/REc and accelerate the progression of HIV-CKD. In addition, we will identify the most relevant signaling pathways involved in these processes, and define how drugs that block the selected pathways affect the progression of HIV-CKD in young mice.