METH and the Neuropathogenesis of SIV Infection

University Of Nebraska Medical Center, Omaha NE

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Abstract

We propose to use quantitative proteomics approaches to study the interactions between simian immunodeficiency virus (SIV) and methamphetamine (METH) in the central nervous system (CNS) of rhesus monkeys. This proposal builds on our previous works for examining the SIV infected brains of rhesus monkeys for biomarker discovery using transcriptomics (gene array) and metabolomics (mass spectrometry) based technologies. For this project, we will perform hypothesis-based studies building on the wealth of data generated in functional proteomics at the University of Nebraska Medical Center (UNMC, Drs. Howard Gendelman, Project 1 and Pawel Ciborowski, Project 3). Our working hypothesis is that in the presence of METH, the harmful effects of SIV on the CNS are increased: when SIV and METH are joined there are dual and interacting untoward effects on CNS function and neuronal viability. Furthermore, since the proteome is broadly affected during disease, we believe that the use proteomics methodologies in the rhesus monkey/SIV/METH model will enable us to explore distinct and synergistic CNS disease mechanisms. We will utilize both unbiased and directed approaches to study how the effects of SIV on the primate brain are affected by METH. These studies are designed to utilize optimal samples for such discovery and follow-up validation, minimizing experimental confounds and directly studying the targets of SIV and METH, as well as accessible biofluids. In combination with the in vitro systems in H. Gendelman's Project ,1 and clinical samples in P. Ciborowski's Project 3, these nonhuman primate studies will form the necessary bridge between the projects as well as allow us to directly assess, in the most accessible and valid system, the target structures in the brain. Given the growing epidemic of METH use, and its relatively frequent abuse in the HIV infected population, this work is relevant to public health in the US. Knowledge about how METH is toxic to the brain in the setting of HIV infection will be useful not only in discouraging METH use, but in obtaining disease-specific markers that can be used for diagnosis and guiding therapeutic interventions.