title: HIV-TAT protein upregulates expression of multidrug resistance protein 1 in the blood-brain barrier.
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.
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Hong
authors.initials: H
authors.lastname: Pu
authors.forename: Ibolya E
authors.initials: IE
authors.lastname: Andras
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Eum
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamauchi
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hennig
authors.forename: Michal
authors.initials: M
authors.lastname: Toborek
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D020805:Central Nervous System Viral Diseases / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015696:Gene Products, tat; D012333:RNA, Messenger; D054322:tat Gene Products, Human Immunodeficiency Virus