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Open AccessArticle

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

1
San Diego Biomedical Research Institute, San Diego, CA 92121, USA
2
Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
3
Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia
4
Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, QLD 4029, Australia
5
School of Medicine, Department of Biomedical Sciences, University of California Riverside, Riverside, CA 92521, USA
6
Parexel International, Glendale, CA 91206, USA
*
Author to whom correspondence should be addressed.
Viruses 2020, 12(4), 426; https://doi.org/10.3390/v12040426
Received: 2 March 2020 / Revised: 27 March 2020 / Accepted: 1 April 2020 / Published: 9 April 2020
(This article belongs to the Special Issue HIV-1 Transcription Regulation)
Methamphetamine (Meth) abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein, trans-activator of transcription (Tat), has been described to induce changes in brain gene transcription that can result in impaired reward circuitry, as well as in inflammatory processes. In transgenic mice with doxycycline-induced Tat protein expression in the brain, i.e., a mouse model of neuroHIV, we tested global gene expression patterns induced by Meth sensitization. Meth-induced locomotor sensitization included repeated daily Meth or saline injections for seven days and Meth challenge after a seven-day abstinence period. Brain samples were collected 30 min after the Meth challenge. We investigated global gene expression changes in the caudate putamen, an area with relevance in behavior and HIV pathogenesis, and performed pathway and transcriptional factor usage predictions using systems biology strategies. We found that Tat expression alone had a very limited impact in gene transcription after the Meth challenge. In contrast, Meth-induced sensitization in the absence of Tat induced a global suppression of gene transcription. Interestingly, the interaction between Tat and Meth broadly prevented the Meth-induced global transcriptional suppression, by maintaining regulation pathways, and resulting in gene expression profiles that were more similar to the controls. Pathways associated with mitochondrial health, initiation of transcription and translation, as well as with epigenetic control, were heavily affected by Meth, and by its interaction with Tat in anti-directional ways. A series of systems strategies have predicted several components impacted by these interactions, including mitochondrial pathways, mTOR/RICTOR, AP-1 transcription factor, and eukaryotic initiation factors involved in transcription and translation. In spite of the antagonizing effects of Tat, a few genes identified in relevant gene networks remained downregulated, such as sirtuin 1, and the amyloid precursor protein (APP). In conclusion, Tat expression in the brain had a low acute transcriptional impact but strongly interacted with Meth sensitization, to modify effects in the global transcriptome. View Full-Text
Keywords: transgenic Tat mouse; methamphetamine; transcriptome transgenic Tat mouse; methamphetamine; transcriptome
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MDPI and ACS Style

Basova, L.V.; Kesby, J.P.; Kaul, M.; Semenova, S.; Garibaldi Marcondes, M.C. Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization. Viruses 2020, 12, 426.

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