HIV-1 infected peripheral blood mononuclear cells modulate the fibrogenic activity of hepatic stellate cells through secreted TGF-β and JNK signaling

• Published in: PloS one Vol. 9; no. 3; p. e91569
• Main Authors: Gupta, Deepti, Rani, Manjusha, Khan, Nabab, Jameel, Shahid
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.03.2014; Public Library of Science (PLoS)
• Subjects: Angiogenesis; Bioinformatics; Biology and life sciences; Blood; Cell culture; Cell Line; Cell Line, Transformed; Cell proliferation; Cell Proliferation - drug effects; Cirrhosis; Cluster Analysis; Culture Media, Conditioned - pharmacology; Extracellular matrix; Fibrosis; Gene Expression Profiling; Gene Expression Regulation; Genetic engineering; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; HIV; HIV-1; Human immunodeficiency virus; Humans; In vitro methods and tests; Inflammation; Intracellular signalling; JNK protein; Kinases; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - virology; Liver; Liver cirrhosis; Liver diseases; Lymphocytes T; Macrophages; MAP Kinase Signaling System - drug effects; Markers; Medicine and Health Sciences; MicroRNAs - genetics; miRNA; NF-kappa B - metabolism; Peripheral blood mononuclear cells; Reverse transcription; Rodents; Signal transduction; Stellate cells; Transforming Growth Factor beta - biosynthesis; Viruses; Western blotting; India
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0091569

Patients with liver disease infected with the human immunodeficiency virus (HIV) exhibit accelerated progression of hepatic fibrosis and liver cirrhosis compared to uninfected individuals. We studied the effects of soluble factors secreted by HIV-infected peripheral blood mononuclear cells (PBMCs) on hepatic stellate cells (HSCs), which are central mediators of liver fibrosis. An in vitro model was used in which a HSC line, LX2, was treated with culture supernatants of human PBMCs infected with macrophage tropic (R5) or T cell tropic (X4) strains of HIV-1. Quantitative reverse transcription PCR (qRT-PCR) and western blotting were used to assess the expression of fibrogenic and proinflammatory markers; LX2 proliferation and intracellular signaling pathways were also studied. A qRT-PCR based miRNome array was used for comparative miRNA profiling of LX2 cells treated with infected PBMC culture supernatants. Pro-fibrogenic, angiogenic and proinflammatory markers, and proliferation of LX2 cells were increased following exposure to culture supernatants from HIV-1 infected PBMCs. The profiling of miRNAs in LX2 cells treated with culture supernatants from HIV-1 R5- or X4-infected PBMCs showed 66 and 22 miRNAs respectively, to be significantly altered compared to mock-treated LX2 cells. While different sets of miRNAs were altered in the two cases, bioinformatics analyses predicted these to be associated with common pathways, including TGF-β signaling and extracellular matrix receptor interaction pathways. HIV infection creates a favorable milieu for the activation of hepatic stellate cells and increased hepatic fibrosis. We identify some regulatory molecules important for these effects.