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Paradoxically, many candidate HIV\u20101 neurotoxins also possess the ability to activate nuclear factor\u2010kappa B (NF\u2010\u03baB), which has a potent pro\u2010survival effect in primary neurons. The present study explored this conundrum and investigated why NF\u2010\u03baB might fail to protect neurons that are exposed to candidate HIV\u20101 neurotoxins. Here, we evaluated the ability of virus\u2010depleted conditioned medium produced by HIV\u20101\u2010infected human macrophages (HIV\u2010MCMs) to modulate NF\u2010\u03baB activity in neurons. We demonstrated that HIV\u2010MCMs inhibit the normal signaling pathways that lead to NF\u2010\u03baB activation in neurons. This inhibitory effect of HIV\u2010MCM is dependent upon the presence of HIV\u20101 Tat, which activates glycogen synthase kinase (GSK)\u20103\u03b2 in neurons. Activation of GSK\u20103\u03b2, in turn, results in modification of the NF\u2010\u03baB subunit RelA at serine 468, thereby regulating the physical interaction of RelA with histone deacetylase\u20103 corepressor molecules. Furthermore, neutralization of Tat or inhibition of GSK\u20103\u03b2 activity prevents neuronal apoptosis induced by HIV\u2010MCM. We conclude that HIV\u20101 Tat may compromise neuronal function and fate by interfering with normal survival pathways subserved by NF\u2010\u03baB. These findings may have important therapeutic implications for the management of HIV\u20101\u2010associated dementia.<\/jats:p>","DOI":"10.1111\/j.1460-9568.2006.04813.x","type":"journal-article","created":{"date-parts":[[2006,5,31]],"date-time":"2006-05-31T15:32:27Z","timestamp":1149089547000},"page":"2623-2634","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Human immunodeficiency virus\u2010encoded Tat activates glycogen synthase kinase\u20103\u03b2 to antagonize nuclear factor\u2010\u03baB survival pathway in neurons"],"prefix":"10.1111","volume":"23","author":[{"given":"Ziye","family":"Sui","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynn F.","family":"Sniderhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shongshan","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katarzyna","family":"Kazmierczak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Reisinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Attila D.","family":"Kov\u00e1cs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary Jane","family":"Potash","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Dewhurst","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harris A.","family":"Gelbard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjay B.","family":"Maggirwar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,5,31]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-2396(200002)35:2<151::AID-SYN8>3.0.CO;2-P"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.26.15895"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.18.6672"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.20.7065-7077.2001"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1067859"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-19-08466.2002"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-4547(20000701)61:1<21::AID-JNR3>3.0.CO;2-7"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C400442200"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2000.0741384.x"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-199712000-00006"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1368"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1062374"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(02)00558-2"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.22.10738-10745.2001"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.10.5274-5277.2002"},{"key":"e_1_2_7_17_1","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1128\/jvi.70.3.1384-1389.1996","article-title":"Extracellular human immunodeficiency virus type 1 Tat protein is associated with an increase in both NF\u2010kappa B binding and protein kinase C activity in primary human astrocytes","volume":"70","author":"Conant K.","year":"1996","journal-title":"J. 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