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  • In conclusion the present study demonstrated that peripheral


    In conclusion, the present study demonstrated that peripheral nerve exposure to HIV gp120 increased the expression levels of the P2Y12 receptor in DRG SGCs and enhanced mechanical and thermal hyperalgesia in rat models. Up-regulation of the P2Y12 receptor in DRG SGCs further promoted the release of pro-inflammatory cytokines. Upregulation of IL-1β, TNF-R1 and GFAP may facilitate the abnormal signal between neuron and SGC in DRG and lead to pain behaviors induced by gp120. Reduction of the P2Y12 receptor in DRG SGCs decreased upregulation of IL-1β, TNF-R1 and GFAP, reduced p-Akt, and inhibited abnormal signal between neuron and SGC in DRG of gp120-treated rats. Therefore, reduction of the P2Y12 receptor in DRG SGCs decreased hyperalgesia in gp120-treated rats.
    Conflict of interests
    Introduction Remarkable progress has been made in curbing the HIV/AIDS epidemic worldwide over the last two decades. The expansion of access to highly active antiretroviral urat1 inhibitor therapy (HAART) globally has led to a significant decline in HIV-related mortality [1,2]. Accumulating evidence suggests that chronic HIV infection and its treatment leads to premature aging [3]. Significant age-related clinical comorbidities have emerged in people living with HIV, including abnormal lipid metabolism, increased risk of cardiovascular disease, neurocognitive disorders, and osteoporosis with fragility fractures [[4], [5], [6], [7]]. Mesenchymal stem urat1 inhibitor (MSC) are essential for physiological tissue repair and immunomodulation [[8], [9], [10]]. Some of the observed HIV-associated comorbidities may be driven by interruptions in normal MSC biology. The HIV structural protein gag p55 modulates MSC differentiation toward a pro-adipogenic (and less osteogenic) phenotype by regulating bone-morphogenic protein (BMP)-2 and runt-related transcription factor (RUNX)-2 activity. Similarly, MSCs treated with serum from HIV infected individuals altered its osteogenic and adipogenic differentiation [11,12]. This in turn reduces new bone development and increases fat formation, leading to osteoporosis and dyslipidemia. In a HIV-transgenic mouse model, MSCs showed impaired differentiation capacity toward osteoblasts (OBs) and less favorable outcome after transplantation into mice with acute renal injury compared to MSCs from control mice [13]. Glycoprotein gp120 binds to CD4 receptors (together with CCR5 or CXCR4 co-receptors) on the surface of susceptible human cells, leading to membrane fusion between virion and host cell and consequent viral entry. In subsequent life cycles of the HIV virus, gp120 is expressed on the surface of infected host cells and is incorporated into the membrane of newly budding virus particles [14]. Despite effective HIV viral load suppression with HAART, there is persistent low-level HIV replication or production of HIV proteins (including gp120) [15,16]. Gp120 may contribute to HIV protein-induced pathologic effects and clinical comorbidities including osteoporosis, pulmonary emphysema, cardiovascular disease and dementia, putatively by inducing cellular apoptosis or disrupting MSC differentiation [12,[17], [18], [19], [20]]. Cysteine (C)-X-C motif chemokine receptor 4 (CXCR4) is the primary transmembrane receptor for signaling chemokine stromal cell-derived factor-1 (SDF-1) [21,22]. This G-protein-coupled-receptor (GPCR) is vital for signal transduction in regulating cell proliferation, migration and differentiation upon association with its ligand SDF-1. CXCR4 and SDF-1 knockout mice die in utero or perinatally with defects in the developing brain, heart, vasculature and haemopoetic tissues [[23], [24], [25]]. The SDF-1/CXCR4 pathway also plays a crucial role in the osteogenic differentiation of mesenchymal progenitors [26,27]. Conditional inactivation of CXCR4 in osteoblastic precursors led to significant impairment of OB development, retardation in bone development and growth in the mouse skeleton [28]. Gp120 has been reported to inhibit SDF-1 induced chemotaxis, putatively by downregulating the expression and function of CXCR4 in monocytes, B cells and T cells [[29], [30], [31]]. There is no data on the impact of gp120 on CXCR4 expression and migration in MSCs.