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| Publication Abstract Display | | Type: Poster | | Title: Effects of methamphetamine on the epigenetic regulation of HIV-1 in the human brain. | | Authors: Desplats P, Dumaop W, Letendre S, Grant I, Masliah E | | Date: 05-29-2012 | | Abstract:Methamphetamine (METH) is a highly addictive psychostimulant abused worldwide; its use is particularly high among persons with HIV infection. The interactions between METH and HIV are yet not completely understood. HIV + METH abusers present more cognitive abnormalities, higher plasma viral loads and more neurological damage than non-abusers. The potentiation of HIV neurodegeneration by METH may be mediated by different molecular mechanisms, including calcium dysregulation, oxidative stress and inflammation. Moreover, METH exposure alters DNA methylation, histone acetylation and gene expression in animal models. DNA methylation is directly linked to regulation of HIV-1 latency, while histone deacetylation is needed to sustain silencing of integrated provirus. The goal of this study was to investigate the effects of METH on the epigenetic regulation of HIV-1 expression in the human brain. We studied 30 postmortem frontal cortex samples from persons dying with HIV of whom n = 15 had histories of METH abuse (HIV + METH+) and n = 15 did not (HIV + METH-). Analysis of DNMT1 expression by qPCR showed increased mRNA levels in HIV + METH + cases. Profiling of DNMT3B, an enzyme that has been reported to have redundant functions to DNMT1 in the adult brain, showed that METH abuse did not alter its expression. Analysis of the status of global methylation in the brain showed an increase in methylation in the HIV + METH + group. Taken together our results suggest that METH-induced epigenetic changes in the human brain might be mediated by increase expression of DNMT1. Better understanding of the molecular mechanisms that govern HIV1 infection in the brain in the context of drug abuse are crucial in the design of therapeutic interventions. This work was supported by Pilot Project Grant PST3TP1 (to PD) from the Translational Methamphetamine AIDS Research Center (P50 DA26306 to IG) and NIH Grants MH62962 (to EM) and California NeuroAIDS Tissue Network U01 MH83506 (to IG). |
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