Document Detail


HIV-TAT protein upregulates expression of multidrug resistance protein 1 in the blood-brain barrier.
MedLine Citation:
PMID:  16395283     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Kentaro Hayashi; Hong Pu; Ibolya E Andras; Sung Yong Eum; Atsushi Yamauchi; Bernhard Hennig; Michal Toborek
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2005-12-14
Journal Detail:
Title:  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism     Volume:  26     ISSN:  0271-678X     ISO Abbreviation:  J. Cereb. Blood Flow Metab.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-07-25     Completed Date:  2006-08-30     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  8112566     Medline TA:  J Cereb Blood Flow Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1052-65     Citation Subset:  IM    
Affiliation:
Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA.
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MeSH Terms
Descriptor/Qualifier:
Acquired Immunodeficiency Syndrome / complications,  drug therapy,  genetics,  metabolism*
Animals
Antiretroviral Therapy, Highly Active
Astrocytes / cytology,  metabolism,  virology
Blood-Brain Barrier / metabolism*,  virology
Cells, Cultured
Central Nervous System Viral Diseases / drug therapy,  etiology,  genetics,  metabolism*
Endothelial Cells / metabolism,  virology
Gene Products, tat / genetics,  metabolism*
HIV-1 / genetics,  metabolism*
Humans
Male
Mice
P-Glycoprotein / biosynthesis*,  genetics
Protein Biosynthesis / drug effects,  genetics
RNA, Messenger / biosynthesis,  genetics
Up-Regulation* / drug effects,  genetics
tat Gene Products, Human Immunodeficiency Virus
Grant Support
ID/Acronym/Agency:
AA013843/AA/NIAAA NIH HHS; MH072567/MH/NIMH NIH HHS; MH63022/MH/NIMH NIH HHS; NS39254/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Gene Products, tat; 0/P-Glycoprotein; 0/RNA, Messenger; 0/tat Gene Products, Human Immunodeficiency Virus

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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