Methamphetamine modulates gene expression patterns in monocyte derived mature dendritic cells: implications for HIV-1 pathogenesis.
BACKGROUND
The US is currently experiencing a grave epidemic of methamphetamine use as a recreational drug, and the risk for HIV-1 infection attributable to methamphetamine use continues to increase. Recent studies show a high prevalence of HIV infection among methamphetamine users. Dendritic cells (DCs) are potent antigen presenting cells that are the initial line of defense against HIV-1 infection. In addition, DCs also serve as reservoirs for HIV-1 and function at the interface between the adaptive and the innate immune systems, which recognize and internalize pathogens and subsequently activate T cells. Exposure to methamphetamine results in modulation of immune functional parameters that are necessary for host defense. Chronic methamphetamine use can cause psychiatric co-morbidity, neurological complications, and can alter normal biological processes and immune functions. Limited information is available on the mechanisms by which methamphetamine may influence immune function. This study explores the effect of methamphetamine on a specific array of genes that may modulate immune function. We hypothesize that methamphetamine treatment results in the immunomodulation of DC functions, leading to dysregulation of the immune system of the infected host. This suggests that methamphetamine has a role as a cofactor in the pathogenesis of HIV-1.


METHODS
We used the high-throughput technology of gene microarray analysis to understand the molecular mechanisms underlying the genomic changes that alter normal biological processes when DCs are treated with methamphetamine. Additionally, we validated the results obtained from microarray experiments using a combination of quantitative real-time PCR and Western blot analysis.


RESULTS
These data are the first evidence that methamphetamine modulates DC expression of several genes. Methamphetamine treatment alters categories of genes that are associated with chemokine regulation, cytokinesis, signal transduction mechanisms, apoptosis, and cell cycle regulation. This report focuses on a selected group of genes that are significantly modulated by methamphetamine treatment and that have been associated with HIV-1 pathogenesis.


CONCLUSIONS
The purpose of this study was to identify genes that are unique and/or specific to the complex immunomodulatory mechanisms that are altered as a result of methamphetamine abuse in HIV-1-infected patients. These studies will help to identify the molecular mechanisms that underlie methamphetamine toxicity, and several functionally important classes of genes have emerged as targets in methamphetamine-mediated immunopathogenesis of HIV-1. Identification of novel DC-specific and methamphetamine-responsive genes that modulate several biological, molecular, and signal transduction functions may serve as methamphetamine- and/or HIV-1-specific drug targets.
Mahajan
Supriya D
SD
Department of Medicine, Division of Allergy, Immunology, and Rheumatology, Buffalo General Hospital, Buffalo, New York 14203, USA. smahajan@buffalo.edu
Hu
Zihua
Z
Reynolds
Jessica L
JL
Aalinkeel
Ravikumar
R
Schwartz
Stanley A
SA
Nair
Madhavan P N
MP
D000328:Adult; D019969:Amphetamine-Related Disorders / Q000235:genetics / Q000276:immunology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D007109:Immunity / Q000235:genetics*; D008694:Methamphetamine / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D019707:Receptors, Chemokine / Q000235:genetics
D000697:Central Nervous System Stimulants; D018925:Chemokines; D016207:Cytokines; D019707:Receptors, Chemokine; D008694:Methamphetamine