Project Summary Despite the dramatic improvement in HIV-associated morbidity and mortality from combination antiretroviral therapy, a number of challenges remain including the long- term persistence of viral reservoirs and the persistence of inflammation that results in end organ damage despite therapy, including chronic kidney disease (CKD). Furthermore, it remains unclear as to the major routes of infection of cells intrinsic to the kidney. Aims 1 and 2 will define the molecules and pathways involved in viral entry, and the steps initiating a robust inflammatory response. Aim 3 will explore the role of macrophages and dendritic cells in facilitating and sustaining the infection of cells in the kidney. Aim 4 will explore the inflammatory consequences of persistence of the virus in renal tubule epithelial cells (RTE). These aims utilize in vitro monocytes-RTE modeling, primary urine derived RTE as well as a humanized mouse model to study both entry and downstream responses. The defined pathways of inflammation will be validated by examination of biopsies from HIV-infected individuals. The information to be gained will impact a major theme in both HIV and chronic kidney disease research, which is understanding the mechanisms that drive chronic inflammation and kidney disease progression and will facilitate the design of better strategies to prevent CKD.