Ethanol potentiates HIV-1 gp120-induced apoptosis in human neurons via both the death receptor and NMDA receptor pathways.
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.
Chen
Wei
W
Center for Human Virology and Biodefense, Division of Infectious Diseases and Environmental Medicine, Thomas Jefferson University, 1020 Locust Street, Suite 329, Philadelphia, PA 19107, USA.
Tang
Zhonghua
Z
Fortina
Paolo
P
Patel
Pritesh
P
Addya
Sankar
S
Surrey
Saul
S
Acheampong
Edward A
EA
Mukhtar
Muhammad
M
Pomerantz
Roger J
RJ
D015526:AIDS Dementia Complex / Q000209:etiology / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D000431:Ethanol / Q000633:toxicity*; D020869:Gene Expression Profiling; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000187:drug effects* / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects* / Q000502:physiology*; D048015:TNF Receptor-Associated Factor 5 / Q000235:genetics
D015699:HIV Envelope Protein gp120; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018124:Receptors, Tumor Necrosis Factor; D048015:TNF Receptor-Associated Factor 5; D000431:Ethanol