PROJECT SUMMARY With the widespread use of combination antiretroviral agents, the incidence of HIV-associated nephropathy (HIVAN) has dramatically decreased in the recent years. Yet, the prevalence of chronic kidney disease (CKD) and end-stage kidney disease in patients living with HIV remains high, suggesting that HIV predisposes patients to increased risk for chronic kidney disease. Indeed, several lines of evidence from recent epidemiological and animal model studies indicate that concurrent HIV infection and age-related comorbidities, such as diabetes mellitus, have a synergistic effect on the incidence of chronic kidney disease, thereby necessitating an examination of mechanisms by which HIV infection even at low viral load accelerates the progression of CKD. Among the HIV-1 viral proteins, we previously showed that HIV viral protein R (Vpr) can induce cell cycle dysregulation, apoptosis, and polyploidy in renal tubular cells. However, the importance and consequences of Vpr-mediated cell cycle arrest and polyploidy has not been fully explored in the setting of kidney disease. In this proposal, we will further dissect the mechanisms dictating the cell fates of Vpr- expressing renal tubular using in vitro approaches (Aim 1). Similarly, using transgenic mice expressing Vpr in renal tubular epithelial cells, we will characterize the cell cycle dysregulation and gene expression at single-cell levels, and determine whether the pharmacological intervention of cell cycle dysregulation can attenuate kidney disease progression in this model, as well as in HIVAN mouse model, Tg26 (Aim 2). To complement the findings in Aims 1 and 2, we will assess the expression of genes and cell cycle regulators in kidney biopsy samples of HIV+ CKD patients (Aim 3). We will also perform transcriptomic profiling for comparative analyses with findings in murine kidneys. Our results will provide a better understanding of the underlying molecular mechanisms by which chronic HIV infection accelerates the progression of CKD and a proof-of-concept for novel target treatment for CKD in HIV patients.