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 < or = 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.

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Alzheimer's disease (AD), the most common cause of dementia, has few clinical similarities to HIV-1-associated dementia (HAD). However, genes were identified related among these dementias. Discovering correlations between gene function, expression, and structure in the human genome continues to aid in understanding the similarities between pathogenesis of these two dementing disorders. The current work attempts to identify relationships between these dementias in spite of their clinical differences, based on genomic structure, function, and expression. In this comparative study, the NCBI Entrez Genome Database is used to detect these relationships. This approach serves as a model for future diagnosis and treatment in the clinical arena as well as suggesting parallel pathways of disease mechanisms. Identifying a correlation among expression, structure, and function of genes involved in pathogenesis of these dementing disorders, may assist to understand better their interaction with each other and the human genome.

Abstract:We analyzed gene expression in neurons from 16 cases divided into four groups, ie, human immunodeficiency virus (HIV)-associated dementia (HAD)/HIV encephalitis (HAD/ HIVE), HAD alone, HIVE alone, and HIV positive alone. We produced the neurons using laser capture microdissection from cryopreserved basal ganglia (specifically globus pallidus). Gene expression in pooled neurons from each case was analyzed on GE CodeLink Microarray chips with 55,000 gene fragments per chip. One-way analysis of variance showed significant changes in expression of 197 genes among the four groups (P , 0.005). The three groups, ie, HAD/HIVE, HAD alone, and HIVE alone, were compared with the HIV-positive group using Fisher's least significant difference test, and associated gene expression changes were assigned to each of the three comparisons. Identified genes were associated with 159 functional categories and many of the genes had more than one function. The functional groups included adhesion,

The human immunodeficiency virus type-1 (HIV-1) gp160 (gp120-gp41 complex) trimer envelope (ENV) protein is a potential vaccine candidate for HIV/AIDS. HIV-1 vaccine development has been problematic and charge polarity as well as sequence variation across clades may relate to the difficulties. Further obstacles are caused by sequence variation between blood and brain-derived sequences, since the brain is a separate compartment for HIV-1 infection. We utilize a threedimensional residue measure of solvent exposure, accessible surface area (ASA), which shows that major segments of gp120 and gp41 known structures are solvent exposed across clades. We demonstrate a large percent sequence polarity for solvent exposed residues in gp120 and gp41. The range of sequence polarity varies across clades, blood, and brain from different geographical locations. Regression analysis shows that blood and brain gp120 and gp41 percent sequence polarity range correlate with mean Shannon entropy. These results point to the use of protein modifications to enhance HIV-1 ENV vaccines across multiple clades, blood, and brain. It should be noted that we do not address the issue of protein glycosylation here; however, this is an important issue for vaccine design and development.AbbreviationsHIV-1 - human immunodeficiency virus type 1, AIDS - acquired immunodeficiency syndrome, ENV - envelope, gp160 - 160,000d glycoprotein, gp120 - 120,000d glycoprotein, gp41 - 41,000d glycoprotein, LANL - Los Alamos National Laboratories, PDB - Protein Data Bank, HVTN - STEP HIV vaccine trial, AA - amino acids, MSA - multiple sequence alignment, ASA - accessible surface area, SNPs- single nucleotide polymorphisms, HAART - Highly Active Antiretroviral Therapy, CCR5 - C-C chemokine receptor type 5, CNS - central nervous system, HIVE - HIV encephalitis, P - polarity, NP - non-polarity, CTL - cytotoxic T lymphocyte, NIAID - National Institute of Allergy and Infectious Diseases.

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