Drug abuse and neuropathogenesis of HIV infection: role of DC-SIGN and IDO Madhavan P.N. Nair * , Stanley A. Schwartz, Supriya D. Mahajan, Chubin Tsiao, Ram P. Chawda, Robert Whitney, Bindukumar B. Don Sykes, Ross Hewitt 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, United States Accepted 30 August 2004 Abstract 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. D 2004 Published by Elsevier B.V. 1. Introduction Dendritic cells (DC) are the first line of defense against HIV infection and are the first cellular compo- nents in the immune system to recognize any infection including human immunodeficiency virus-type 1 (HIV-1). Immature DC (IDC) are potent antigen presenting cells which engulf microbes and antigens. Upon interaction with antigens, DC become activated or mature and then migrate to regional lymphoid tissues where the pro- cessed antigens are presented to naive CD4 T cells subsequently enabling T cell activation (Steinman and Germain, 1998; Banchereau and Steinman, 1998). DC play a critical role in harboring HIV and possibly infecting neighbouring T cells and facilitate the virus dissemination through blood–brain barrier (BBB) causing CNS dysfunctions (Po ¨hlmann et al., 2001; Bashirova et al., 2001). The first step in the infection process is the attachment of virus to the susceptible target cells and it is known that several proteins play major roles in the processes. (Geijtenbeek and van Kooyk, 2003; Geijten- beek and Torensma, 2001; Bashirova et al., 2003) Recent discovery of DC specific intercellular adhesion molecule-3 (ICAM-3) grabbing nonintegrin, DC-SIGN, 0165-5728/$ - see front matter D 2004 Published by Elsevier B.V. doi:10.1016/j.jneuroim.2004.08.040 Abbreviations: BBB, blood–brain barrier; BE, benzoylecgonine; BMVEC, brain microvascular endothelial cells; DC-SIGN, dendritic cell (DC)-specific C type ICAM-3 grabbing nonintegrin; HIV-1, human immunodeficiency virus-type 1; ICAM-3, intercellular adhesion mole- cule-3; MDC, mature dendritic cell; PBMC, peripheral blood mononuclear cells; DC, dendritic cells; ICAM-1, intercellular adhesion molecule-1; IDO, indolamine 2,3-dioxygenase; MMP, matrix metalloproteinases; MT-MMPs, membrane-type matrix metalloproteinases. * Corresponding author. Tel.: +716 859 2985; fax: +716 859 2999. E-mail address: mnair@buffalo.edu (M.P.N. Nair). Journal of Neuroimmunology 157 (2004) 56 – 60 www.elsevier.com/locate/jneuroim