Polyploidy and Mitotic Cell Death are Two Distinct HIV-1 Vpr-Driven Outcomes in Renal Tubule Epithelial Cells

Given the emerging epidemic of renal disease in HIV+ patients and the fact that HIV DNA and RNA persist in the kidneys of HIV+ patients despite therapy, it is necessary to understand the role of direct HIV-1 infection of the kidney. HIV-associated kidney disease pathogenesis is attributed in large part to viral proteins. Expression of Vpr in renal tubule epithelial cells (RTECs) induces G2 arrest, apoptosis and polyploidy. The ability of a subset of cells to overcome the G2/M block and progress to polyploidy is not well understood. Polyploidy frequently associates with a bypass of cell death and disease pathogenesis. Given the ability of the kidney to serve as a unique compartment for HIV-1 infection, and the observed occurrence of polyploid cells in HIV+ renal cells, it is critical to understand the mechanisms and consequences of Vpr-induced polyploidy.

Here I determined effects of HIV-1 Vpr expression in renal cells using highly efficient transduction with VSV.G pseudotyped lentiviral vectors expressing Vpr in the HK2 human tubule epithelial cell line. Using FACS, fluorescence microscopy, and live cell imaging I show that G2 escape immediately precedes a critical junction between two distinct outcomes in Vpr+ RTECs: mitotic cell death and polyploidy. Vpr+ cells that evade aberrant mitosis and become polyploid have a substantially higher survival rate than those that undergo complete mitosis, and this survival correlates with enrichment for polyploidy in cell culture over time. Further, I identify a novel role for ATM kinase in promoting G2 arrest escape and polyploidy in this context. In summary, my work identifies ATM-dependent override of Vpr-mediated G2/M arrest as a critical determinant of cell fate Vpr+ RTECs. Further, our work highlights how a poorly understood HIV mechanism, ploidy increase, may offer insight into key processes of reservoir establishment and disease pathogenesis in HIV+ kidneys.

Connecting Mentally Ill Detainees in Large Urban Jails with Community Care.

Large urban jails have become a collection point for many persons with severe mental illness. Connections between jail and community mental health services are needed to assure in-jail care and to promote successful community living following release. This paper addresses this issue for 2855 individuals with severe mental illness who received community mental health services prior to jail detention in King County (Seattle), Washington over a 5-year time period using a unique linked administrative data source. Logistic regression was used to determine the probability that a detainee with severe mental illness received mental health services while in jail as a function of demographic and clinical characteristics. Overall, 70 % of persons with severe mental illness did receive in-jail mental health treatment. Small, but statistically significant sex and race differences were observed in who received treatment in the jail psychiatric unit or from the jail infirmary. Findings confirm the jail's central role in mental health treatment and emphasize the need for greater information sharing and collaboration with community mental health agencies to minimize jail use and to facilitate successful community reentry for detainees with severe mental illness.