Drug abuse and neuropathogenesis of HIV infection: role of DC-SIGN and IDO.
Dendritic cells are the critical mediators of various immune responses and are the first line of defense against any infection including HIV. They play a major role in harboring HIV and the subsequent infection of T cells and passage of virus through the blood-brain barrier (BBB). The recently discovered DC-specific, CD4-independent HIV attachment receptor, DC-SIGN, and T-cell suppressing factor, indolamine 2,3-dioxygenase (IDO), are known to play a critical role in the immuno-neuropathogenesis of HIV infection. Since brain microvascular cells (BMVEC) express dendritic cell (DC)-specific C type ICAM-3 grabbing nonintegrin (DC-SIGN), it is possible that DC-SIGN may play a critical role in human immunodeficiency virus-type 1 (HIV-1) infection and migration of infected DC across BBB. Matrix metalloproteinases (MMPs) are proteolytic enzymes known to be responsible for maintenance, turnover and integrity of extracellular matrix. Our results show that cocaine upregulates IDO and DC-SIGN expression by DC. Further, cocaine upregulates DC-SIGN and MMPs in BMVEC supporting the hypothesis that cocaine causes membrane permeability facilitating endothelial transmigration of infected DC in to the CNS. Targeting DC-SIGN and IDO with specific monoclonal antibodies, inexpensive synthetic antagonists, antisense oligonucleotides and siRNA may lead to develop novel treatment strategies particularly in high-risk populations such as cocaine users.
Nair
Madhavan P N
MP
Department of Medicine, Division of Allergy, Immunology, and Rheumatology and State University of New York and Buffalo General Hospital, Kaleida Health System 100 High Street, Buffalo, NY 14203, USA. mnair@buffalo.edu
Schwartz
Stanley A
SA
Mahajan
Supriya D
SD
Tsiao
Chubin
C
Chawda
Ram P
RP
Whitney
Robert
R
Don Sykes
Bindukumar B
BB
Hewitt
Ross
R
D000779:Anesthetics, Local / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015658:HIV Infections / Q000150:complications* / Q000201:enzymology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D019966:Substance-Related Disorders / Q000150:complications*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D000779:Anesthetics, Local; D015815:Cell Adhesion Molecules; D003042:Cocaine; D049308:Dioxygenases; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D037181:Lectins, C-Type; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C402225:MMP17 protein, human