HIV-1 exposure is associated with methamphetamine (Meth) abuse. These two factors synergize in aggravating neuroAIDS symptoms and disease progression. One of the important consequences of Meth on innate immune cells is to change the balance of reactive oxygen species (ROS) and induce inflammatory markers, such as CCR5 and RANTES. These changes are believed to be dopamine-dependent, but we have observed that both ROS and CCR5 can be induced in dopamine-free systems. Interestingly, ROS in the CNS can signal the increase of NFkB levels and phosphorylation, and directly induce activation of promoters of inflammatory molecules. On the other hand, HIV Tat, which also induces ROS, has been shown to potentiate glial activation and neuronal damage induced by Meth and other drugs of abuse. HIV Tat, but not Meth, increases several TATA-box binding components in macrophages in vitro, suggesting that it can have a modulatory effect on promoters of inflammatory molecules that bear a TATA-box promoter domain in the promoter. We hypothesize that transcriptional signaling triggered by Meth-induced ROS interact with a TATA-box-dependent modulatory mechanism in the presence of HIV Tat. We propose to explore the role of ROS-induced pathways in the upregulation of CCR5 and RANTES on astrocytes and microglia by Meth and Tat, aiming to identify the players in a dopamine-independent mechanism. We will also investigate whether the induction of TATA-box binding elements is at the basis of the ability of HIV Tat to modulate ROS and inflammatory markers in the CNS, affect immune cell infiltration and interfere with drug-related stereotypic behaviors. Using an original approach we expect to unveil a basic mechanism of interaction between HIV and Meth in the aggravation of CNS pathology, which will open a new line of investigation with a translational reach.

Public Health Relevance

Currently, we don't understand all of the cellular mechanisms whereby Meth upregulates inflammatory molecules such as CCR5 and RANTES and the mechanisms by which the interaction between Meth use and HIV exposure enhance brain viral load and pathology. We have evidence of a role for Meth-induced ROS in regulating CCR5 expression in a dopamine-independent fashion, and we have identified an ability of HIV Tat to upregulate TATA-box binding elements, which are regulatory components that can interfere with the expression of 10% of genes with expression high variability, such as chemokines, chemokine receptors, and several early response inflammatory genes. We will investigate whether ROS-induced transcription factors in the presence of Meth are modulated by a TATA-box based mechanism triggered by HIV Tat, altering the phenotype of glial cells towards a higher expression of CCR5 and RANTES, exacerbating the inflammatory milieu and promoting viral replication: these are potentially novel modes of regulation of molecules such as CCR5 in the context of drugs of abuse and HIV, relevant for immune function in the brain, and open an original translational perspective for understanding the susceptibility to inflammatory neuropathology in amphetamine users.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA036164-02
Application #
8669961
Study Section
Special Emphasis Panel (ZDA1-GXM-A (08))
Program Officer
Satterlee, John S
Project Start
2013-07-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$473,750
Indirect Cost
$223,750
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Bortell, Nikki; Basova, Liana; Semenova, Svetlana et al. (2017) Astrocyte-specific overexpressed gene signatures in response to methamphetamine exposure in vitro. J Neuroinflammation 14:49
Kesby, James P; Najera, Julia A; Romoli, Benedetto et al. (2017) HIV-1 TAT protein enhances sensitization to methamphetamine by affecting dopaminergic function. Brain Behav Immun 65:210-221
Bortell, Nikki; Flynn, Claudia; Conti, Bruno et al. (2017) Osteopontin Impacts West Nile virus Pathogenesis and Resistance by Regulating Inflammasome Components and Cell Death in the Central Nervous System at Early Time Points. Mediators Inflamm 2017:7582437
Bortell, Nikki; Basova, Liana; Najera, Julia A et al. (2017) Sirtuin 1-Chromatin-Binding Dynamics Points to a Common Mechanism Regulating Inflammatory Targets in SIV Infection and in the Aging Brain. J Neuroimmune Pharmacol :
Najera, Julia A; Bustamante, Eduardo A; Bortell, Nikki et al. (2016) Methamphetamine abuse affects gene expression in brain-derived microglia of SIV-infected macaques to enhance inflammation and promote virus targets. BMC Immunol 17:7
Bortell, Nikki; Najera, Julia A; Sanchez-Alavez, Manuel et al. (2015) In vivo effects of methamphetamine on brown fat reactive oxygen species and mitochondria. Temperature (Austin) 2:453
Bortell, Nikki; Morsey, Brenda; Basova, Liana et al. (2015) Phenotypic changes in the brain of SIV-infected macaques exposed to methamphetamine parallel macrophage activation patterns induced by the common gamma-chain cytokine system. Front Microbiol 6:900
Mediouni, Sonia; Marcondes, Maria Cecilia Garibaldi; Miller, Courtney et al. (2015) The cross-talk of HIV-1 Tat and methamphetamine in HIV-associated neurocognitive disorders. Front Microbiol 6:1164
Marcondes, Maria Cecilia Garibaldi; Ojakian, Ryan; Bortell, Nikki et al. (2014) Osteopontin expression in the brain triggers localized inflammation and cell death when immune cells are activated by pertussis toxin. Mediators Inflamm 2014:358218
Sanchez-Alavez, Manuel; Bortell, Nikki; Galmozzi, Andrea et al. (2014) Reactive oxygen species scavenger N-acetyl cysteine reduces methamphetamine-induced hyperthermia without affecting motor activity in mice. Temperature (Austin) 1:227-241

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