The Human Immunodeficiency Virus 1 (HIV-1) mainly infect CD4+ T cells. It also infects myeloid cells, highly contributing to the chronic inflammation observed in HIV+ patients. Persistence of immune activation could lead to immune cell dysfunction and increased risk of developing HIV-associated malignancies, including Kaposi's Sarcoma (KS). Immune dysregulation and an inflammatory environment are risk factors for KS herpes virus (KSHV) reactivation and KS development. MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by inhibition or degradation of target mRNAs. MiRNAs are implicated in the macrophage maturation as well as their recruitment to inflammatory sites. In addition to their role as intracellular gene regulators, miRNAs can be secreted through exosomes and affect gene expression on recipient cells at distant sites. We isolated CD14+ cells from HIV subjects and healthy controls and polarized toward M1 and M2 phenotypes. Expression analysis of three pre-selected miRNAs revealed, as expected, a strong up-regulation of miR-155-Sp and miR-146a-5p during polarization of the controls cells; however, HIV-derived cells failed to upregulate these two miRNAs. Conversely, miR-223-3p, was more downregulated in macrophages derived from HIV patients compared to controls. As miR-146a and miR-155 play key roles in endotoxin tolerance (a transition state that prevents an excessive immune activation), failure to up-regulate those miRNAs by HIV-derived macrophages upon their activation may indicate a reduced ability of these cells to control inflammatory responses. Indeed, gene expression analysis of polarized macrophages revealed a dysfunctional immune response for both M 1 and M2 macrophages from HIV subjects compared to controls. In addition, we found dysregulated miRNAs in plasma exosomes from HIV subjects with or without KS. We hypothesize that dysregulated miRNA expression in circulating monocytes and exosomes in HIV +-subjects leads to dysfunctional macrophages, contributing to an inflammatory environment and tumor development.
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