The Impact of Marijuana Use on Memory in Patients with HIV/AIDS

The most robust neurocognitive effect of marijuana use is memory impairment. Memory deficits are also high among persons living with HIV/AIDS, and marijuana use among this population is disproportionately common. Yet research examining neurocognitive outcomes resulting from co-occurring marijuana and HIV is virtually non-existent. The primary aim of this case-controlled study was to identify patterns of neurocognitive impairment among HIV patients who used marijuana compared to HIV patients who did not use drugs by comparing the groups on domain T-scores. Participants included 32 current marijuana users and 37 non-drug users. A comprehensive battery assessed substance use and neurocognitive functioning. Among the full sample, marijuana users performed significantly worse on verbal memory tasks compared to non-drug users and significantly better on attention/working memory tasks. A secondary aim of this study was to test whether the effect of marijuana use on memory was moderated by HIV disease progression, but these models were not significant. This study also examined whether the effect of marijuana use was differentially affected by marijuana use characteristics, finding that earlier age of initiation was associated with worse memory performance. These findings have important clinical implications, particularly given increased legalization of this drug to manage HIV infection.

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.