Methamphetamine abuse affects gene expression in brain-derived microglia of SIV-infected macaques to enhance inflammation and promote virus targets.
Methamphetamine (Meth) abuse is a major health problem linked to the aggravation of HIV- associated complications, especially within the Central Nervous System (CNS). Within the CNS, Meth has the ability to modify the activity/function of innate immune cells and increase brain viral loads. Here, we examined changes in the gene expression profile of neuron-free microglial cell preparations isolated from the brain of macaques infected with the Simian Immunodeficiency Virus (SIV), a model of neuroAIDS, and exposed to Meth. We aimed to identify molecular patterns triggered by Meth that could explain the detection of higher brain viral loads and the development of a pro-inflammatory CNS environment in the brain of infected drug abusers.



We found that Meth alone has a strong effect on the transcription of genes associated with immune pathways, particularly inflammation and chemotaxis. Systems analysis led to a strong correlation between Meth exposure and enhancement of molecules associated with chemokines and chemokine receptors, especially CXCR4 and CCR5, which function as co-receptors for viral entry. The increase in CCR5 expression was confirmed in the brain in correlation with increased brain viral load.



Meth enhances the availability of CCR5-expressing cells for SIV in the brain, in correlation with increased viral load. This suggests that Meth is an important factor in the susceptibility to the infection and to the aggravated CNS inflammatory pathology associated with SIV in macaques and HIV in humans.
Cellular and Molecular Neurosciences Department, The Scripps Research Institute, 10550 North Torrey Pines Rd. SR307, La Jolla, CA, 92037, USA.
Julia A
JA
Najera
Cellular and Molecular Neurosciences Department, The Scripps Research Institute, 10550 North Torrey Pines Rd. SR307, La Jolla, CA, 92037, USA.|Present address: Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Eduardo A
EA
Bustamante
Cellular and Molecular Neurosciences Department, The Scripps Research Institute, 10550 North Torrey Pines Rd. SR307, La Jolla, CA, 92037, USA.
Nikki
N
Bortell
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5800, USA.
Brenda
B
Morsey
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5800, USA.
Howard S
HS
Fox
Division of Chemical & Life Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Kingdom of Saudi Arabia.
Timothy
T
Ravasi
Cellular and Molecular Neurosciences Department, The Scripps Research Institute, 10550 North Torrey Pines Rd. SR307, La Jolla, CA, 92037, USA. cmarcond@scripps.edu.
Maria Cecilia Garibaldi
MC
Marcondes
D000818:Animals; D001921:Brain / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D002633:Chemotaxis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008251:Macaca; D008694:Methamphetamine / Q000008:administration & dosage*; D017628:Microglia / Q000276:immunology* / Q000821:virology; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D019966:Substance-Related Disorders / Q000276:immunology* / Q000821:virology; D019562:Viral Load
D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D008694:Methamphetamine
Brain; CCR5; Central nervous system; Human immunodeficiency virus; Inflammation; Methamphetamine; Microglia; NeuroAIDS; Simian immunodeficiency virus