HIV-TAT protein upregulates expression of multidrug resistance protein 1 in the blood-brain barrier

Kentaro Hayashi, H. Pu, Ibolya E. Andras, Sung Yong Eum, Atsushi Yamauchi, Bernhard Hennig, Michal Toborek

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Central nervous system (CNS) complications of human immunodeficiency virus (HIV) infection remain a serious health risk in HIV/acquired immunodeficiency syndrome despite significant advances in highly active antiretroviral therapy (HAART). Specific drugs used for HAART are substrates for the efflux transport systems, such as the multidrug resistance-associated proteins (MRPs), which are present on brain microvascular endothelial cells (BMEC) and astrocytes, that is, the main cell types that form the blood-brain barrier (BBB). Thus, drugs employed in HAART are actively removed from the CNS and do not efficiently inhibit HIV replication in the brain. To study the potential mechanisms of this process, the aim of the present research was to address the hypothesis that HIV Tat protein can contribute to upregulation of MRP expression at the BBB level. Tat is a protein produced and released by HIV-infected cells, which may play an important role in brain vascular pathology in the course of HIV infection. Among the family of MRPs, exposure to Tat specifically induced MRP1 messenger ribonucleic acid and protein expression both in BMEC and astrocytes. These alterations were accompanied by enhanced MRP1-mediated efflux functions. Furthermore, activation of the mitogen-activated protein kinase signaling cascade was identified as the mechanism involved in Tat-mediated overexpression of MRP1. These results indicate that Tat exposure can lead to alterations of the BBB functions and decrease HAART efficacy in the CNS through overexpression of drug efflux transporters.

Original languageEnglish
Pages (from-to)1052-1065
Number of pages14
JournalJournal of Cerebral Blood Flow and Metabolism
Volume26
Issue number8
DOIs
Publication statusPublished - Aug 14 2006

Fingerprint

Human Immunodeficiency Virus Proteins
P-Glycoprotein
Blood-Brain Barrier
Highly Active Antiretroviral Therapy
Multidrug Resistance-Associated Proteins
Up-Regulation
HIV
Central Nervous System
Brain
Virus Diseases
Astrocytes
Endothelial Cells
Pharmaceutical Preparations
tat Gene Products
Virus Replication
Mitogen-Activated Protein Kinases
Blood Vessels
Acquired Immunodeficiency Syndrome
Proteins
RNA

Keywords

  • Blood-brain barrier
  • Brain endothelial cells
  • HAART
  • MAP kinase
  • Multidrug resistance-associated proteins
  • Tat protein

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

Cite this

HIV-TAT protein upregulates expression of multidrug resistance protein 1 in the blood-brain barrier. / Hayashi, Kentaro; Pu, H.; Andras, Ibolya E.; Eum, Sung Yong; Yamauchi, Atsushi; Hennig, Bernhard; Toborek, Michal.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 26, No. 8, 14.08.2006, p. 1052-1065.

Research output: Contribution to journalArticle

Hayashi, Kentaro ; Pu, H. ; Andras, Ibolya E. ; Eum, Sung Yong ; Yamauchi, Atsushi ; Hennig, Bernhard ; Toborek, Michal. / HIV-TAT protein upregulates expression of multidrug resistance protein 1 in the blood-brain barrier. In: Journal of Cerebral Blood Flow and Metabolism. 2006 ; Vol. 26, No. 8. pp. 1052-1065.
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