title: Interactive role of human immunodeficiency virus type 1 (HIV-1) clade-specific Tat protein and cocaine in blood-brain barrier dysfunction: implications for HIV-1-associated neurocognitive disorder.
abstract: In recent years, increasing interest has emerged to assess the human immunodeficiency virus type 1 (HIV-1) clade C viral pathogenesis due to its anticipated spread in the United States and other western countries. Previous studies suggest that clade C is less neuropathogenic than clade B; however, the underlying mechanism is poorly understood. Additionally, the interactive role of drugs of abuse such as cocaine on clade C-associated neuropathogenesis has not been reported. In the current study, we hypothesize that HIV-1 clade-specific Tat proteins exert differential effects on blood-brain barrier (BBB) integrity and cocaine further differentially aggravates the BBB dysfunction. We evaluated the effect of Tat B and Tat C and/or cocaine on the BBB integrity using an in vitro model constructed with primary human brain microvascular endothelial cells (HBMECs) and astrocytes. The BBB membrane integrity was measured by transendothelial electrical resistance (TEER) and paracellular permeability was measured by fluorescein isothiocyanate (FITC)-dextran transport assay and monocytes transmigration across the BBB. Results indicate that Tat B disrupts BBB integrity to a greater extent compared to Tat C and cocaine further differentially exacerbates the BBB dysfunction. This BBB dysfunction was associated with altered expression of tight junction proteins zona occuldens (ZO-1) and junctional adhesion molecule (JAM)-2. Thus, these results for the first time delineate the differential role of Tat B and Tat C and/or cocaine in BBB dysfunction, which may be correlated with the clade-specific differences observed in HIV-1-associated neurological disorders.
authors.affiliation: Department of Immunology, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida 33199, USA.
authors.forename: Nimisha
authors.initials: N
authors.lastname: Gandhi
authors.forename: Zainulabedin M
authors.initials: ZM
authors.lastname: Saiyed
authors.forename: Jessica
authors.initials: J
authors.lastname: Napuri
authors.forename: Thangavel
authors.initials: T
authors.lastname: Samikkannu
authors.forename: Pichili V B
authors.initials: PV
authors.lastname: Reddy
authors.forename: Marisela
authors.initials: M
authors.lastname: Agudelo
authors.forename: Pradnya
authors.initials: P
authors.lastname: Khatavkar
authors.forename: Shailendra K
authors.initials: SK
authors.lastname: Saxena
authors.forename: Madhavan P N
authors.initials: MP
authors.lastname: Nair
mesh_terms: D015526:AIDS Dementia Complex / Q000473:pathology / Q000503:physiopathology* / Q000821:virology; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology* / Q000821:virology; D015153:Blotting, Western; D002199:Capillary Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003042:Cocaine / Q000633:toxicity*; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity*; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology / Q000821:virology; D015870:Gene Expression; D020869:Gene Expression Profiling; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019108:Tight Junctions / Q000187:drug effects / Q000473:pathology / Q000821:virology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000494:pharmacology*
chemical_list: D018765:Dopamine Uptake Inhibitors; D054322:tat Gene Products, Human Immunodeficiency Virus; D003042:Cocaine