INVITED REVIEW Impact of Opiate–HIV-1 Interactions on Neurotoxic Signaling Kurt F. Hauser & Nazira El-Hage & Shreya Buch & Avindra Nath William R. Tyor & Annadora J. Bruce-Keller & Pamela E. Knapp * Springer Science+Business Media 2006 Abstract Opiate drug abuse exacerbates the patho- genesis of human immunodeficiency virus-1 (HIV-1) in the central nervous system through direct actions on glia and neurons. Opiate abuse causes widespread disruption of astroglial and microglial function, and significant increases in astroglial-derived proinflamma- tory cytokines and chemokines, which likely contributes to neuronal dysfunction, death, and HIV encephalitis. Neurons are also directly affected by opiate–HIV-1 interactions. HIV-1 and the viral proteins gp120 and Tat activate multiple caspase-dependent and caspase- independent proapoptotic pathways in neurons involv- ing phosphatidylinositol 3-kinase (PI3 kinase)/Akt, as well as p38, c-Jun N-terminal kinase (JNK) and/or other mitogen-activated protein kinases (MAPKs). Opiates appear to decrease the threshold for HIV-1- mediated neurotoxicity by sending convergent signals that exacerbate proapoptotic events induced by viral and cellular toxic products. The synergistic proinflam- matory and neurotoxic effects of opiate drugs on glia and neurons are largely mediated through 2 opioid receptors, which are expressed by subpopulations of astroglia, microglia, and neurons. Opiate abuse intrin- sically modifies the host response to HIV-1. Identifica- tion of how this occurs is providing considerable insight toward understanding the mechanisms underlying HIV- 1-associated dementia. Key words AIDS . 2-opioid receptors . neurons . astroglia . microglia . neuroimmunology . monocyte chemoattractant protein-1 (MCP-1/CCL2) . apoptosis . p38 mitogen-activated protein kinase (MAPK) . c-Jun N-terminal kinase (JNK) . caspase-3 Introduction Injection drug users are at higher risk for contracting human immunodeficiency virus-1 (HIV-1) infection and for developing neurological and systemic complications (Nath et al. 2000, 2002). In many parts of the world, drug abuse and HIV-1 are interrelated epidemics and AIDS is widely spread through injection drug use or drug-seeking behaviors. Besides providing a mode for viral spread, drug use may intrinsically affect the pathogenesis of HIV-1. Opiates can activate HIV-1 replication in microglial cells and autopsy studies show that HIV-infected opiate users have severe HIV encephalitis (Anthony et al. 2005). Opiate drugs, in particular, intrinsically modulate peripheral immune function and exacerbate the pathogenesis and neurological complications of HIV-1 through direct actions in the central nervous system (CNS) (see Hauser et al. 2005). Opioid–HIV-1 interactions in the CNS are complex, and mediated through direct actions in neurons, astroglia, and microglia. This review examines the cellular mecha- nisms by which opiates interact with HIV-1 in each neural cell type, and discusses how the coordinated neuron–glial interactions contribute to HIV-1 neuropathogenesis. Impact of glial-mediated opiate–HIV-1 interactions on neurons It is well established that glia mediate many of the neurotoxic effects of HIV-1. Microglia, in particular, have been proposed as major contributors to HIV-1 neuropatho- genesis, and the supporting data have been extensively reviewed (Nathanson et al. 1994; Gendelman et al. 1997; Kaul et al. 2001; Persidsky and Gendelman 2003). Although some infection of astrocytes and endothelial cells are reported, HIV-1 is concentrated and retained in brain microglia and infiltrating macrophages, which con- J Neuroimmune Pharmacol (2006) 1:1–9 DOI 10.1007/s11481-005-9000-4 K. F. Hauser (*) I N. El-Hage I S. Buch I A. J. Bruce-Keller I P. E. Knapp Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, 800 Rose Street, Lexington KY 40536-0298, USA e-mail: khauser@uky.edu K. F. Hauser I A. J. Bruce-Keller I P. E. Knapp Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky Medical Center, Lexington, KY 40536, USA A. Nath Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA W. R. Tyor Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA