Interferon-stimulated gene expression in HIV-1 inoculated macrophages and healthy Langerhans cells: The impact of macrophage polarization and Langerhans cell maturation

Abstract

Abstract Background: Antigen presenting cells (APCs) have been extensively studied for their role in human immunodeficiency virus type 1 (HIV-1) infection. HIV-1 is readily recognized by APCs, which subsequently exert a strong antiviral response through induced expression of interferon-stimulated genes (ISGs). Cellular activating processes in APCs can influence the extent of this antiviral response and may alter susceptibility to HIV-1 infection. In this study, we investigated the effect of distinctive activation processes on ISG expression in two types of APC: macrophage polarization and Langerhans cell maturation. Methods: Microarray-based differential gene expression (DGE) analysis was performed to study the effects of M1, M2a and M2 macrophage polarization on ISG expression upon HIV-1 inoculation. Furthermore, we performed RNA-seq of immature and mature Langerhans cells. DGE analysis and weighted gene co-expression network analysis (WGCNA) were performed, comparing ISG expression between immature and mature Langerhans cells derived from healthy donors in absence of HIV-1. Results: HIV-1 inoculation of macrophages led to polarization state-specific gene expression changes: M1 and M2c showed a relatively large and partly overlapping change in ISG expression, whereas M2a remained largely transcriptionally refractive, which was opposite of what was observed in absence of HIV-1. Differential expression of TIMP1 and PLAUR was validated in an independent macrophage set. Mature Langerhans cells were found to differ greatly in their gene expression compared to immature Langerhans cells and intersection of DGE-WGCNA results revealed several maturity state driver ISGs. Conclusion: These findings enhance our understanding of the effects of macrophage polarization and Langerhans cell differentiation on ISG expression and outline various candidate genes for further exploration of their role in HIV-1 pathogenesis.