HIV-1-associated nephropathy (HIVAN) is a major complication of HIV-1 infection, frequently resulting in kidney failure. HIVAN arises due to HIV-1-induced dysregulation of podocytes, the glomerular epithelial cells that establish and maintain the kidney filtration barrier. Host genetic factors are important for the development of HIVAN. The risk of HIVAN is greatest in populations of African ancestry, and is attributable to a genetic variation at the APOL1 locus on chromosome 22. Mouse models of HIVAN enable delineation of dysregulated pathways underlying disease. Identification of HIVAN susceptibility loci in a mouse model, combined with expression quantitative trait locus mapping, has demonstrated that murine HIVAN loci transregulate podocyte gene expression. HIV-1 induces perturbations in podocyte expression response, suggesting that HIV-1 potentially interferes with compensatory pathways that normally restore cellular homeostasis in the face of genetic mutations. These findings present a framework for identification of podocyte transregulators and reconstruction of the molecular networks connecting susceptibility genes to the development of nephropathy.