TY - JOUR
T1 - HIV-TAT protein upregulates expression of multidrug resistance protein 1 in the blood-brain barrier
AU - Hayashi, Kentaro
AU - Pu, Hong
AU - Andras, Ibolya E.
AU - Eum, Sung Yong
AU - Yamauchi, Atsushi
AU - Hennig, Bernhard
AU - Toborek, Michal
PY - 2006/8/14
Y1 - 2006/8/14
N2 - 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.
AB - 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.
KW - Blood-brain barrier
KW - Brain endothelial cells
KW - HAART
KW - MAP kinase
KW - Multidrug resistance-associated proteins
KW - Tat protein
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U2 - 10.1038/sj.jcbfm.9600254
DO - 10.1038/sj.jcbfm.9600254
M3 - Article
C2 - 16395283
AN - SCOPUS:33746576853
SN - 0271-678X
VL - 26
SP - 1052
EP - 1065
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
IS - 8
ER -