Abstract
Macrophages act as reservoirs of human immunodeficiency virus type 1 (HIV-1) and play an important role in its transmission to other cells. HIV-1 Vpr is a multi-functional protein involved in HIV-1 replication and pathogenesis; however, its exact role in HIV-1-infected human macrophages remains poorly understood. In this study, we used a microarray approach to explore the effects of HIV-1 Vpr on the transcriptional profile of human monocyte-derived macrophages (MDMs). More than 500 genes, mainly those involved in the innate immune response, the type I interferon pathway, cytokine production, and signal transduction, were differentially regulated (fold change >2.0) after infection with a recombinant adenovirus expressing HIV-1 Vpr protein. The differential expression profiles of select interferon-stimulated genes (ISGs) and genes involved in the innate immune response, including STAT1, IRF7, MX1, MX2, ISG15, ISG20, IFIT1, IFIT2, IFIT3, IFI27, IFI44L, APOBEC3A, DDX58 (RIG-I), TNFSF10 (TRAIL), and RSAD2 (viperin) were confirmed by real-time quantitative PCR and were consistent with the microarray data. In addition, at the post-translational level, HIV-1 Vpr induced the phosphorylation of STAT1 at tyrosine 701 in human MDMs. These results demonstrate that HIV-1 Vpr leads to the induction of ISGs and expand the current understanding of the function of Vpr and its role in HIV-1 immune pathogenesis.
Highlights
Antigen-presenting cells (APCs) are critical for both innate and adaptive immunity
The DNA content of ZsGreen1-positive cells was analyzed by flow cytometry, which revealed a dramatic increase in the proportion of cells in the G2 phase of the cell cycle in cells infected with Ad-Vpr (21.22% and 70.37% were in the G1 and the G2+M phases, respectively, and the G2+M: G1 ratio was 3.32) compared to cells infected with the control Ad-Zs (54.06% and 23.87% were in the G1 and G2/M phases, respectively, and the G2+M: G1 ratio was 0.44) (Figure 1B)
The data presented are the first analysis of the changes in gene transcription that occur following in vitro infection of human monocyte-derived macrophages (MDMs) with an adenovirus expressing human immunodeficiency virus type 1 (HIV-1) Vpr protein
Summary
Antigen-presenting cells (APCs) are critical for both innate and adaptive immunity. Professional APCs such as macrophages play an integral role in the immune pathogenesis of the human immunodeficiency virus type 1 (HIV-1) [1]. Vpr is a pleiotropic protein that is involved in diverse functions including cell-cycle arrest at the G2/M phase [7], apoptosis [7,8,9], nuclear import of the preintegration complex [10,11,12,13,14], transcriptional activation [15], and splicing [16,17] Vpr performs these functions through interactions with various host cellular factors such as DCAF1, SAP145, p300, and importin-a [8,10,11,12,16,18,19,20,21]
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