{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:02:24Z","timestamp":1778126544424,"version":"3.51.4"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2004,7,23]],"date-time":"2004-07-23T00:00:00Z","timestamp":1090540800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2004,7,23]]},"abstract":"<jats:title>SUMMARY<\/jats:title><jats:p>We reported recently that exposure of human T cells to soluble HIV-1 envelope glycoprotein gp120 induced biologically active tumour necrosis factor (TNF)-\u03b1-related cytokine receptor of activated NF-\u03baB ligand (RANKL), the primary drive to osteoclast differentiation and bone resorption. Furthermore, certain anti-HIV protease inhibitors linked clinically to accelerated bone loss in HIV disease blocked the physiological control of RANKL activity by interferon (IFN)-\u03b3 through inhibition of degradation of the RANKL nuclear adapter signalling protein, TNF receptor associated protein 6 (TRAF6). We now report a series of reciprocal interactions among HIV-1, RANKL and IFN-\u03b3. RANKL augmented HIV replication in acutely and chronically infected cells of T lymphocyte and monocyte lineage, effects which occurred at a transcriptional level in conjunction with activation of NF-\u03baB. TNF-\u03b1 and RANKL were markedly synergistic in induction of HIV. Low pharmacological levels of IFN-\u03b3 (0\u00b775\u20133\u2003ng\/ml) suppressed RANKL-driven enhancement of HIV replication, as did L-T6DP-1, a cell-permeable peptide inhibitor of TRAF6. In contrast, HIV replication induced by TNF-\u03b1 and phorbol ester were not inhibited, and in some cases augmented, by IFN-\u03b3. We conclude that a positive feedback loop exists between RANKL production and HIV replication, which may be relevant to both the pathophysiology of HIV-linked osteopenia and control of HIV growth. This pathway appears distinct from those of other cytokine activators of HIV, with respect to its utilization of TRAF6 and its suppression by IFN-\u03b3. These data raise the possibility that TRAF-specific inhibitory peptides, alone or in conjunction with IFN-\u03b3, could be used to regulate HIV activation in vivo.<\/jats:p>","DOI":"10.1111\/j.1365-2249.2004.02568.x","type":"journal-article","created":{"date-parts":[[2004,8,20]],"date-time":"2004-08-20T10:57:27Z","timestamp":1092999447000},"page":"538-545","source":"Crossref","is-referenced-by-count":25,"title":["Interactions among human immunodeficiency virus (HIV)-1, interferon-<i>\u03b3<\/i>and receptor of activated NF-<i>\u03ba<\/i>B ligand (RANKL): implications for HIV pathogenesis"],"prefix":"10.1093","volume":"137","author":[{"given":"J M","family":"FAKRUDDIN","sequence":"first","affiliation":[{"name":"Laboratory for AIDS Virus Research, Department of Medicine, Weill Medical College of Cornell University, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"LAURENCE","sequence":"additional","affiliation":[{"name":"Laboratory for AIDS Virus Research, Department of Medicine, Weill Medical College of Cornell University, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2004,8,20]]},"reference":[{"key":"2022011223191152300_b1","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/46303","article-title":"Activated T cells regulate bone loss and joint destruction adjuvant arthritis through osteoprotegerin ligand","volume":"402","author":"Kong","year":"1999","journal-title":"Nature"},{"key":"2022011223191152300_b2","doi-asserted-by":"crossref","first-page":"48251","DOI":"10.1074\/jbc.M304676200","article-title":"HIV envelope gp120-mediated regulation of osteoclastogenesis via receptor activator of nuclear factor \u03baB ligand (RANKL) secretion and its modulation by HIV protease inhibitors through interferon-\u03b3\/RANKL cross-talk","volume":"278","author":"Fakruddin","year":"2003","journal-title":"J Biol 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