HIV Type 1 gp120–Induced Expansion of Myeloid Derived Suppressor Cells Is Dependent on Interleukin 6 and Suppresses Immunity

Human immunodeficiency virus type 1 (HIV) infection causes profound immune suppression leading to progressive destruction of the immune system in untreated patients. Recently, a subset of myeloid cells known as myeloid-derived suppressor cells (MDSCs) was found to negatively regulate immune functions [1, 2]. MDSCs express common myeloid markers (CD11b+CD33+HLA-DR−/lo) [1–3] and, depending on the presence of CD15 or CD14, are divided into granulocytic or monocytic subsets, respectively [3–5]. These cells suppress innate and adaptive immunity either by arginase 1 (Arg1), reactive oxygen species (ROS), and reactive nitrogen species generation and/or by mediation of CD4+CD25+FoxP3+ regulatory T-cell (Treg) expansion [6–10]. Expansion and function of MDSCs is regulated by the transcription factor STAT3, which induces expression of antiapoptotic genes and prevents differentiation of myeloid progenitor cells into mature myeloid cells [1]. Considerable research, predominantly performed in animal models, has demonstrated inhibition of antitumor and antimicrobial activity by MDSCs. Additionally, recent evidence suggests that this inhibitory activity is present in patients with certain malignancies [5, 6, 9, 10]. Limited information is available on the role of MDSCs in human infections, including HIV infection. In vitro and in vivo differentiation of MDSCs is regulated by various cytokines, including interleukin 6 (IL-6), interleukin 10 (IL-10), prostaglandins, stem-cell factor, granulocyte macrophage colony-stimulating factor, transforming growth factor β, vascular endothelial growth factor, and tumor necrosis factor α (TNF-α) [8, 9]. Levels of a number of these cytokines, including IL-6, are elevated in serum and cerebrospinal fluid of HIV–infected persons. Levels of IL-6 decline following successful suppression of replicating HIV with administration of combination antiretroviral therapy, suggesting the potential detrimental effects of IL-6 in HIV pathogenesis [11–14]. In the present study, we hypothesized that IL-6 produced during HIV infection drives the expansion of MDSCs, which contributes to HIV–associated immune suppression. Our findings indicate that when peripheral blood mononuclear cells (PBMCs) are exposed to HIV gp120, inhibitory MDSCs expand in an IL-6–dependent manner, suppressing T-cell functions and inducing regulatory T-cell expansion. Additionally, an increased number of MDSCs was observed in HIV–infected persons with detectable viral loads.