CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Poster and Themed Discussion Abstracts

680 SOCS-1/TRAF-6 UP-REGULATION IN BONE IMPAIRMENT IN HIV+ PATIENTS ON EFFECTIVE CART Elvira S. Cannizzo , Federico A. Cazzaniga, Esther Merlini, Camilla Tincati, Lidia Gazzola, Nathalie Iannotti, Angelo Del Sole, Antonella d’Arminio Monforte, Giulia Marchetti Univ of Milan, Milan, Italy Background: Accelerated osteopenia/osteoporosis affects up to 30% HIV+ patients on virally-effective cART, yet the pathogenic molecular mechanism(s) remain poorly understood. Osteoclasts (OCs) from HIV transgenic rats express high levels of suppressor of cytokine signaling-1 (SOCS-1) and tumor necrosis factor receptor-associated factor-6 (TRAF-6), leading to increased osteoclastogenesis through IFN-g pathway inhibition. We investigated osteoclastogenesis and SOCS-1/TRAF-6 in OCs of HIV+cART+ patients with and without reduced bone mineral density (BMD). Methods: We consecutively enrolled 50 HIV+ patients on virally-effective cART (HIV-RNA <40cp/ml) matched for viro-immunologic/demographic features (Fig1a): 16 with normal BMD (nBMD) by dual x-ray absorptiometry (osteopenia, Tscore -1/-2.5; osteoporosis, Tscore <-2.5), 34 with reduced BMD (rBMD, including osteopenic and osteoporotic patients) (Fig1a); 10 HIV-negative healthy controls (HIV-). Circulating OC precursors (OCPs; CD14+CD11b+CD51/61+) were studied by flow-cytometry. OCs were differentiated from peripheral blood-purified CD14+ supplemented with M-CFS and RANKL (8 days). OCs differentiation/maturation was evaluated by TRAP staining and dentin resorption. OC RANK, SOCS-1, TRAF6 expression were analyzed by Real-Time PCR and Western-Blot with and without IFN- g stimulation (100 U,2 h). Kruskal-Wallis was used. Results: HIV+rBMD presented significantly higher OCPs vs HIV+ nBMD (p=.029). CD14+ cultures from HIV+rBMD were enriched in large, multinucleated TRAP+OCs versus nBMD and HIV- (Fig.1b), as confirmed by TRAP quantification (p=.03; p=.04). Interestingly, despite equal RANK expression, OCs from HIV+rBMD expressed significantly higher SOCS-1 and TRAF-6: > 2.61, >1.62 fold vs HIV-, respectively, significantly higher than nBMD (p=0.027; p=0.05). IFN-γ challenge resulted in 1.2-fold decrease and 2.5-fold increase of SOCS-1 mRNA in HIV-OCs and HIV+OCs, respectively (p=0.04 for HIV+IFNy+ vs HIV-IFNy+). Conclusion: HIV+rBMD patients show increased circulating OCPs and OCs ex-vivo differentiation, indicating heightened osteoclastogenesis in treated HIV+ osteopenic/ osteoporotic patients. Relevantly, we show that OCs from HIV+rBMD express high SOCS-1/TRAF-6 levels, that are further upregulated upon IFN-γ challenge. Together, these findings identify deregulated SOCS-1/TRAF-6 as molecular pro-osteoclastogenesis pathway that might be sustained by abnormal interferon-mediated inflammation in successfully-treated HIV

CROI 2017 295