HIV-1 Infected Peripheral Blood Mononuclear Cells Modulate the Fibrogenic Activity of Hepatic Stellate Cells through Secreted TGF-β and JNK Signaling

Abstract

Background and AimsPatients 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.MethodsAn 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.ResultsPro-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.ConclusionsHIV 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.

Mechanisms of Accelerated Liver Fibrosis Progression during HIV Infection

“…In contrast to hepatocytes, HIV directly infects HSCs, and this infection has been shown to promote HSC collagen I expression and secretion of the proinflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) 28,29. The HIV gp120 protein also induces activation of tissue-inhibitor metalloproteinase (TIMP).…”

Circulating MicroRNAs as a marker for liver injury in human immunodeficiency virus patients

“…This study demonstrated that this is also the case in HIV patients. It has been shown previously that HIV infection promotes liver fibrogenesis . The highly abundant liver‐specific miRNA‐122 plays an important role in the HCV life cycle by directly interacting with viral RNA and thus stimulating HCV .…”

“…It has been shown previously that HIV infection promotes liver fibrogenesis. 21 The highly abundant liverspecific miRNA-122 plays an important role in the HCV life cycle by directly interacting with viral RNA and thus stimulating HCV. 33,34 Recently, miRNA-122 up-regulation was described in primary peripheral blood mononuclear cells of 12 HIV/HCV coinfected patients and correlated with key gene targets.…”

“…miRNAs have been investigated with regard to HIV‐1 replication, and a number of publications underlined the pivotal role of miRNAs in suppressing HIV infection . However, to date circulating miRNA have not been investigated in HIV patients with regard to liver injury.…”

“…[15][16][17][18][19] miRNAs have been investigated with regard to HIV-1 replication, and a number of publications underlined the pivotal role of miRNAs in suppressing HIV infection. 16,[20][21][22] However, to date circulating miRNA have not been investigated in HIV patients with regard to liver injury. The present study aims to identify liver injury and relevant liver fibrosis related to circulating miRNAs in HIV patients with and without concomitant viral infection.…”