We have previously shown that HIV infection of renal epithelial cells is required but not sufficient to induce HIV-associated nephropathy (HIVAN), and that genetic factors responsible for susceptibility and progression are likely to be downstream of the viral entry event. We previously established the kidney as a replication-competent compartment; however, we do not understand the dynamics of infection. We hypothesize that infiltrating T cells and macrophages transfer HIV to renal epithelial cells through cell-cell contact. The transfer of viral RNA induces a strong innate immune response, and the subsequent release of chemoattractants recruits more infected cells. The transfer of HIV RNA also results in the translation of viral proteins that drive host cellular responses. These maladaptive host responses lead to disease in genetically susceptible individuals. We hypothesize that renal pathogenesis in response to HIV infection derives from myriad complex interactions of the HIV-1 proteins Nef and Vpr with host signaling pathways.
Project #1 has previously identified four loci that are associated with susceptibility to HIVAN in the murine model (HIVAN1-4). This project will identify the HIVAN1 and HIVAN2 genes, and validate the observed gene associations in human kidney disease.
Project #2 will perform viral quasispecies analysis to determine whether urine reflects the renal compartment, and to compare viral sequence evolution in urine and PBMC. This project will continue to characterize the mechanism of viral entry and the downstream effects of HIV-1 VPR expression in tubular epithelial cells.
Project #3 will explore the role of the host response genes in HIVAN pathogenesis. This project will determine the importance of Sidekick-1 in mediating the collapsing glomerulosclerosis of HIVAN using a transgenic model, and the role of Podocan in HIVAN pathogenesis using a novel knockout mouse. In addition, this project has demonstrated induction of an inflammatory cascade in tubular epithelial cells infected with HIV, and will extend these studies to characterize the expression of Toll-like receptors in response to the transfer of HIV RNA from T cells.
Project #4 will use a systems biology approach to characterize the downstream transcription factor and gene regulatory networks involved in the development of HIVAN, integrating data from all four projects. Results from these studies will improve our understanding of the pathogenesis of HIVAN and HIV infection, identify new strategies for diagnosis and therapy, and provide new insights into racial disparities in susceptibility to kidney disease.
