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Neuronal apoptosis may result from activation of the intrinsic (mitochondrial\/<jats:italic>bcl-2<\/jats:italic>regulated) or extrinsic (death receptor) pathways, although which pathway predominates in CNS HIV infection is unknown. Apoptosis initiated by the intrinsic pathway is typically blocked by antiapoptosis Bcl-2 family proteins, such as Bcl-2 and Bcl-xL, but whether these can block HIV\/macrophage-induced neuronal apoptosis is unknown. To determine the potential role of the Bcl-2 family in HIV\/macrophage-induced neuronal apoptosis, we developed a unique in vitro model, utilizing the NT2 neuronal cell line, primary astrocytes and macrophages, and primary CNS HIV type 1 (HIV-1) isolates. We validated our model by demonstrating that NT2.N neurons are protected against HIV-infected macrophages by<jats:italic>N<\/jats:italic>-methyl-<jats:sc>d<\/jats:sc>-aspartate (NMDA) glutamate receptor antagonists, similar to effects seen in primary neurons. We then established stable NT2.N neuronal lines that overexpress Bcl-2 or Bcl-xL (NT2.N\/bcl-2 and NT2.N\/bcl-xL, respectively) and determined their sensitivity to macrophages infected with primary R5, X4, and R5\/X4 HIV-1 isolates. We found that NT2.N\/bcl-2 and NT2.N\/bcl-xL neurons were resistant to apoptosis induced by either R5, X4, or R5\/X4 isolates and that resistance was abrogated by a Bcl-2 antagonist. Thus, the NMDA receptor\/<jats:italic>bcl-2<\/jats:italic>-regulated apoptotic pathway contributes significantly to HIV\/macrophage-induced neuronal apoptosis, and Bcl-2 family proteins protect neurons against the spectrum of primary HIV-1 isolates. Modulation of<jats:italic>bcl-2<\/jats:italic>gene expression may therefore offer adjunctive neuroprotection against development of AIDS dementia.<\/jats:p>","DOI":"10.1128\/jvi.76.18.9407-9419.2002","type":"journal-article","created":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T19:36:19Z","timestamp":1033500979000},"page":"9407-9419","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":69,"title":["Development of a Human Neuronal Cell Model for Human Immunodeficiency Virus (HIV)-Infected Macrophage-Induced Neurotoxicity: Apoptosis Induced by HIV Type 1 Primary Isolates and Evidence for Involvement of the Bcl-2\/Bcl-xL-Sensitive Intrinsic Apoptosis Pathway"],"prefix":"10.1128","volume":"76","author":[{"given":"Wei","family":"Chen","sequence":"first","affiliation":[{"name":"Departments of Neurology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jerrold","family":"Sulcove","sequence":"additional","affiliation":[{"name":"Departments of Neurology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Frank","sequence":"additional","affiliation":[{"name":"Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salman","family":"Jaffer","sequence":"additional","affiliation":[{"name":"Departments of Neurology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hakan","family":"Ozdener","sequence":"additional","affiliation":[{"name":"Departments of Neurology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis L.","family":"Kolson","sequence":"additional","affiliation":[{"name":"Departments of Neurology"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.1995.tb01053.x"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90230-N"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004010050409"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0320(19970301)27:3<275::AID-CYTO10>3.0.CO;2-Q"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90508-N"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.16.1.395"},{"key":"e_1_3_2_8_2","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1046\/j.1471-4159.2000.0741613.x","volume":"74","year":"2000","unstructured":"Cheung, N. 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