Ethanol potentiates HIV-1 gp120-induced apoptosis in human neurons via both the death receptor and NMDA receptor pathways

• Published in: Virology (New York, N.Y.) N.Y.), 2005-03, Vol.334 (1), p.59-73
• Main Authors: Chen, Wei, Tang, Zhonghua, Fortina, Paolo, Patel, Pritesh, Addya, Sankar, Surrey, Saul, Acheampong, Edward A., Mukhtar, Muhammad, Pomerantz, Roger J.
• Format: Article
• Language: English
• Subjects: AIDS Dementia Complex - etiology; AIDS Dementia Complex - pathology; Apoptosis; Apoptosis - drug effects; Cells, Cultured; CNS; Ethanol; Ethanol - toxicity; Gene Expression Profiling; gp120; HIV Envelope Protein gp120 - physiology; HIV-1; HIV-1 - pathogenicity; Human immunodeficiency virus 1; Humans; Neurons; Neurons - drug effects; Neurons - pathology; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - physiology; Receptors, Tumor Necrosis Factor - drug effects; Receptors, Tumor Necrosis Factor - physiology; TNF Receptor-Associated Factor 5 - genetics
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2005.01.014

Neuronal loss is a hallmark of AIDS dementia syndromes. Human immunodeficiency virus type I (HIV-1)-specific proteins may induce neuronal apoptosis, but the signal transduction of HIV-1 gp120-induced, direct neuronal apoptosis remains unclear. Ethanol (EtOH) is considered to be an environmental co-factor in AIDS development. However, whether EtOH abuse in patients with AIDS increases neuronal dysfunction is still uncertain. Using pure, differentiated, and post-mitotic NT2.N-derived human neurons, we investigated the mechanisms of HIV-1 and/or EtOH-related direct neuronal injury and the molecular interactions between HIV-1-specific proteins and EtOH. It was demonstrated that NT2.N neurons were susceptible to HIV-1 Bal (R5-tropic strain) gp120-induced direct cell death. Of importance, EtOH induced cell death in human neurons in a clinically-relevant dose range and EtOH strongly potentiated HIV-1 gp120-induced neuronal injury at low and moderate concentrations. Furthermore, this potentiation of neurotoxicity could be blocked by N-methyl- d-aspartate (NMDA) receptor subunit 2B (NR2B) antagonists. We analyzed human genomic profiles in these human neurons, using Affymetrix genomics technology, to elucidate the apoptotic pathways involved in HIV-1- and EtOH-related neurodegeneration. Our findings indicated significant over-expression of selected apoptosis functional genes. Significant up-regulation of TRAF5 gene expression may play an essential role in triggering potentiation by EtOH of HIV-1 gp120-induced neuronal apoptosis at early stages of interaction. These studies suggested that two primary apoptotic pathways, death receptor (extrinsic) and NMDA receptor (intrinsic)-related programmed cell-death pathways, are both involved in the potentiation by EtOH of HIV-1 gp120-induced direct human neuronal death. Thus, these data suggest rationally-designed, molecular targets for potential anti-HIV-1 neuroprotection.