[Frontiers in Bioscience 11, 1774-1793, May 1, 2006]

Gene Chromosomal Organization and Expression in Cultured Human Neurons Exposed to Cocaine and HIV-1 proteins gp120 and tat: Drug Abuse and NeuroAIDS

Paul Shapshak 1-5, Robert Duncan 6, Avindra Nath 7, Jadwiga Turchan 8, Pandjassarame Kangueane 9, Solveig AM Shapshak, Hector Rodriguez 1, E. Margarita Duran 1, Fabiana Ziegler 1, Eric Amaro 1, Apple Lewis1, Alejandro Rodriguez 1, Alireza Minagar 10-12, Wade Davis 13, Raman Seth 14,15, Fatten F. Elkomy15, Francesco Chiappelli 16, and Toni Kazic 14,15

1 Department of Psychiatry & Behavioral Sciences, 2 Department of Neurology, 3 Department of Pathology, 4 McDonald Foundation GeneTeam of the Department of Pediatrics, 5 Comprehensive Drug Research Center, 6 Department of Epidemiology, University of Miami School of Medicine, Miami, FL 33136, 7 Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street Baltimore, MD 21287, 8 Department of Anatomy, University of Kentucky School of Medicine, Lexington, KY, 9 School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore, 10Department of Neurology, 11 Psychiatry, 12Anesthesiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71130, 13 Department of Statistical Science, Baylor University, Waco, TX, 14 Department of Computer Science, School of Engineering, 15 Department of Health Management and Informatics, School of Medicine, University of Missouri, Columbia, MO 65211, 16 Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, CA 90095

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. AIDS Dementia
2.2. Inflammation
2.3. Neuronal damage
2.4. Drugs, HIV-1, neural cells, and NeuroAIDS
3. Materials & Methods
3.1. Neuron isolation and culture
3.2. Gene expression analysis
3.3. Statistical analysis
3.4. Gene-chromosome and pathway analysis
4. Results
4.1. Gene identification
4.2. Gene groups
4.3. Pathways
4.4. Gene chromosome maps
5. Discussion
5.1. Gene expression in drug abuse and NeuroAIDS
5.2. Hypothesis 1. Genes identified related to drug abuse and HIV-1 protein treatments are associated with transcription isolation
5.3. Hypothesis 2. Drug abuse and HIV-1 proteins coerce transcription overload
6. Conclusions and future directions
7. Acknowledgements
8. References

1. ABSTRACT

As a model for Neuropsychiatric dysfunction in NeuroAIDS due to HIV-1 infection and drug abuse, we analyzed gene expression in human neurons treated with cocaine and HIV-1 proteins tat and envelope (env). One-way ANOVA showed statistically significant genes among the treatment groups (p ≤ 0.0005). The identified genes were then subjected to a "stepwise" analysis using a repeated measures ANOVA to discover genes with parallel response group profiles across the treatment conditions. These groups were then analyzed using a repeated measures ANOVA to assess treatment main effects and gene-by-treatment interactions within groups. One-way ANOVA produced 35 genes that were significantly associated across all treatment conditions. Factorial analysis of each gene found statistically significant differences: 30 - tat, 17 - cocaine, 10 - env, 6 - tat/env, 6 - coc/env, and 4 - coc/tat. Analyses across genes found three sets of four genes, one set of three genes, and three sets of two genes with parallel profiles. Identified genes had functions included signaling, immune related, and transcription control. The genes were not stochastically arranged on the chromosomes, were in proximity to each other, and to other genes involved in neuropsychiatric diseases. We hypothesize that these genes fall in transcriptionally isolated groups and that abused drugs and HIV-1 proteins trigger transcription overload, coerced expression that may result in damage to the chromosome's control and organization of chromatin transcription machinery.