title: Developmental regulation of P-glycoprotein activity within thymocytes results in increased anti-HIV protease inhibitor activity.
abstract: The thymus harbors HIV-1 and supports its replication. Treatment with PI-containing ART restores thymic output of naïve T cells. This study demonstrates that CXCR4-using WT viruses are more sensitive to PI in fetal thymcocytes than mature T cells with average IC(50) values for two PIs, RTV and IDV, of 1.5 nM (RTV) and 4.4 nM (IDV) in thymocytes versus 309.4 nM (RTV) and 27.3 nM (IDV) in mature T cells. P-gp activity, as measured using Rh123 efflux and quantitation of P-gp mRNA, increased with thymocyte maturation into CD4 and CD8 lineage T cells. P-gp activity is developmentally regulated in the thymus. Thymocytes developed increased levels of P-gp activity as maturation from DP to SP CD4 or CD8 T cells occurred, although CD4 T cells acquired activity more rapidly. Reduced P-gp activity in thymocytes is one mechanism for effectiveness of PI therapy in suppressing viral replication in the thymus and in reconstitution of naïve T cells, particularly among children receiving PI-containing ART.
authors.affiliation: Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of South Florida, St. Petersburg, Florida 33701, USA.
authors.forename: Soichi
authors.initials: S
authors.lastname: Haraguchi
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Ho
authors.forename: Matthew
authors.initials: M
authors.lastname: Morrow
authors.forename: Maureen M
authors.initials: MM
authors.lastname: Goodenow
authors.forename: John W
authors.initials: JW
authors.lastname: Sleasman
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D012333:RNA, Messenger