Cocaine increases human immunodeficiency virus type 1 neuroinvasion through remodeling brain microvascular endothelial cells.
Cocaine is a suspected cofactor in human immunodeficiency virus (HIV)-associated dementia but cocaine's effects are not clear. Herein the authors describe investigations of the mechanisms by which cocaine increases HIV-1 invasion through brain microvascular endothelial cells (BMVECs). Cocaine binds to a site on BMVECs, which is not a biogenic amine transporter, a binding site for estrogen, or a muscarinic receptor and for which benztropine and tamoxifen have the highest affinity. Cocaine treatment of BMVECs disrupts intercellular junctions and induces cell ruffling, which could account for their increased permeability and decreased electrical resistance. HIV-1 enters BMVECs by macropinocytosis and is transported to lysosomes and inactivated. In cocaine-treated BMVECs, the virus enters and persists in large cytoplasmic "lakes." Cocaine exposure of BMVECs up-regulates transcription of genes important in cytoskeleton organization, signal transduction, cell swelling, vesicular trafficking, and cell adhesion. The toxicity of cocaine for the blood-brain barrier may lead to increased virus neuroinvasion and neurovascular complications of cocaine abuse.
Fiala
Milan
M
Department of Medicine, West Los Angeles VA Medical Center and UCLA School of Medicine, Los Angeles, CA 90095, USA. Fiala@ucla.edu
Eshleman
Amy J
AJ
Cashman
John
J
Lin
Justin
J
Lossinsky
Albert S
AS
Suarez
Vannina
V
Yang
Wendy
W
Zhang
Jun
J
Popik
Waldemar
W
Singer
Elyse
E
Chiappelli
Francesco
F
Carro
Eva
E
Weinand
Martin
M
Witte
Marlys
M
Arthos
James
J
D001812:Blood-Brain Barrier / Q000821:virology; D001921:Brain / Q000098:blood supply; D002478:Cells, Cultured; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D004730:Endothelium, Vascular / Q000502:physiology / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D010539:Permeability; D010873:Pinocytosis; D011960:Receptors, Estrogen / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects
D011960:Receptors, Estrogen; D011976:Receptors, Muscarinic; D003042:Cocaine