Role of microbial translocation in HIV infected patients during suppressive Antiretroviral Therapy (cART) and causal relationship with HIV-driven bone impairment

Stefania E. Cannizzo

Short title : Microbial translocation and causal relationship with HIV driven osteoporosis
Background: Up to 30% of cART-treated HIV-infected patients show a premature osteopenia/osteoporosis. Dysregulated osteoclastogenesis has been correlated with SOCS-1 and TRAF-6 expressions. We investigated osteoclastogenesis and SOCS-1/TRAF-6 pathways in human peripheral blood-derived OCs of HIV positive cART-treated patients with and without reduced BMD. Microbial translocation (MT) and microRNAs play a crucial role in the pathogenesis of HIV age-associated degenerative clinical conditions .We aim to investigate how MT by miR-155 regulation, possibly through SOCS-1/TRAF-6 pathways up regulation, might affect osteoclastogenesis in a cohort of chronic HIV-infected subjects with different degree of bone impairment.
Material and Methods: 80 HIV+ treated patients and 20 HIV-negative healthy controls will be consecutively enrolled. Bone assessment will be defined by dual x ray absorptiometry (DXA). OCs will be differentiated from peripheral blood-purified CD14+ cells (+M-CFS and +RANKL) for 8 days. OCs differentiation will be evaluated by TRAP staining.SOCS-1/TRAF6 expressions will be analyzed by qPCR and Western-Blot. LPS, Endocab, sCD14, IL-10 will be quantified on plasma samples. MicroRNA 155 expression will be quantified by qPCR and SOCS-1/TRAF-6 expression will be evaluated after antagomir 155 transfection.
Preliminary Results: We measured circulating OC precursor (OCPs, CD14+,CD11b, CD51/61+) from 50 HIV+ treated patients. HIV+ rBMD patients displayed significantly higher circulating OCPs vs HIV+ nBMD (p=.029). ).Numerous large TRAP+ OCs were identified in CD14+ cultures from HIV+ rBMD patients, whereas less OCs appeared in the CD14+ cultures from HIV+ nBMD patients and from HIV negative controls (Fig.1). OCs from HIV+ rBMD expressed higher SOCS-1 and TRAF-6 levels: respectively >2.61 and >1.62 fold vs basal levels of HIV negative; significantly higher than nBMD (p=0.0027 and p=0.05) (Fig.2).
Conclusions: HIV+ rBMD patients show increased circulating OCPs and OCs ex-vivo differentiation, indicating heightened osteoclastogenesis in treated-HIV+ osteopenic/osteoporotic patients, with disruption of the physiological homeostatic equilibrium between bone formation and resorption. Understanding the mechanisms of HIV-1-induced bone loss and the role played by over-expression of SOCS-1 will be critical for early detection of changes in BMD and in developing effective therapy. We speculate that elevated MT and SOCS-1 levels may be predictive for reduced BMD and an increased likelihood of HIV-1 induced fragility fractures.

Simone Agnello
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