Gp120 modulates the biology of human hepatic stellate cells: A link between HIV infection and liver fibrogenesis

Raffaele Bruno, Sara Galastri, Paolo Sacchi, Serena Cima, Alessandra Caligiuri, Raffaella DeFranco, Stefano Milani, Sandra Gessani, Laura Fantuzzi, Francesco Liotta, Francesca Frosali, Giorgio Antonucci, Massimo Pinzani, Fabio Marra

Research output: Contribution to journalArticle

Abstract

Objective: In patients with hepatitis C virus (HCV)/HIV coinfection, a faster progression of liver fibrosis to cirrhosis has been reported. In this study, an investigation was carried out to determine whether gp120, an HIV envelope protein, modulates the biology of human hepatic stellate cells (HSCs), key cell types in the pathogenesis of fibrosis. Methods: Myofibroblastic HSCs were isolated from normal human liver tissue. Gene expression was measured by real-time PCR. Cell migration was assessed in Boyden chambers. Intracellular signalling pathways were evaluated using phosphorylation-specific antibodies or by transfection of a reporter plasmid. Results: Transcripts for the chemokine receptors CCR5 and CXCR4, which bind gp120, were detectable in human HSCs. Upon exposure to M-tropic recombinant gp120, which binds CCR5, a significant increase in HSC chemotaxis was observed (1.6±0.3-fold, p=0.03). The effects of gp120 were prevented by protein inactivation. gp120 also resulted in a significant increase in secretion (1.5±0.3-fold, p=0.03) and gene expression (1.47±0.13-fold, p=0.02) of the proinflammatory chemokine monocyte chemoattractant protein-1, and in increased gene expression of tissue inhibitor of metalloprotease-1 and interleukin-6 (2.03±0.57-fold, p=0.02). gp120-induced migration required Akt activation. gp120 also induced activation of nuclear factor-κB (NF-κB) and p38MAPK. Preincubation of HSCs with TAK779, a CCR5 receptor antagonist, prevented gp120-mediated chemotaxis and monocyte chemoattractant protein-1 secretion. Expression of CCR5 was detectable in areas of inflammation and fibrogenesis in liver biopsies of patients with HCV/HIV co-infection. Conclusions: This study shows that HIV gp120 modulates different aspects of HSC biology, including directional cell movement and expression of proinflammatory cytokines. These results identify a direct pathway possibly linking HIV infection with liver fibrogenesis via envelope proteins.

Original languageEnglish
Pages (from-to)513-520
Number of pages8
JournalGut
Volume59
Issue number4
DOIs
Publication statusPublished - Apr 2010

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Hepatic Stellate Cells
HIV Infections
Liver
HIV Envelope Protein gp120
Chemokine CCL2
Chemotaxis
Coinfection
Gene Expression
Hepacivirus
Cell Movement
Fibrosis
Chemokine Receptors
Metalloproteases
Chemokines
Liver Cirrhosis
Transfection
Cell Biology
Real-Time Polymerase Chain Reaction
Interleukin-6
Proteins

ASJC Scopus subject areas

  • Gastroenterology

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Gp120 modulates the biology of human hepatic stellate cells : A link between HIV infection and liver fibrogenesis. / Bruno, Raffaele; Galastri, Sara; Sacchi, Paolo; Cima, Serena; Caligiuri, Alessandra; DeFranco, Raffaella; Milani, Stefano; Gessani, Sandra; Fantuzzi, Laura; Liotta, Francesco; Frosali, Francesca; Antonucci, Giorgio; Pinzani, Massimo; Marra, Fabio.

In: Gut, Vol. 59, No. 4, 04.2010, p. 513-520.

Research output: Contribution to journalArticle

Bruno, R, Galastri, S, Sacchi, P, Cima, S, Caligiuri, A, DeFranco, R, Milani, S, Gessani, S, Fantuzzi, L, Liotta, F, Frosali, F, Antonucci, G, Pinzani, M & Marra, F 2010, 'Gp120 modulates the biology of human hepatic stellate cells: A link between HIV infection and liver fibrogenesis', Gut, vol. 59, no. 4, pp. 513-520. https://doi.org/10.1136/gut.2008.163287
Bruno, Raffaele ; Galastri, Sara ; Sacchi, Paolo ; Cima, Serena ; Caligiuri, Alessandra ; DeFranco, Raffaella ; Milani, Stefano ; Gessani, Sandra ; Fantuzzi, Laura ; Liotta, Francesco ; Frosali, Francesca ; Antonucci, Giorgio ; Pinzani, Massimo ; Marra, Fabio. / Gp120 modulates the biology of human hepatic stellate cells : A link between HIV infection and liver fibrogenesis. In: Gut. 2010 ; Vol. 59, No. 4. pp. 513-520.
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abstract = "Objective: In patients with hepatitis C virus (HCV)/HIV coinfection, a faster progression of liver fibrosis to cirrhosis has been reported. In this study, an investigation was carried out to determine whether gp120, an HIV envelope protein, modulates the biology of human hepatic stellate cells (HSCs), key cell types in the pathogenesis of fibrosis. Methods: Myofibroblastic HSCs were isolated from normal human liver tissue. Gene expression was measured by real-time PCR. Cell migration was assessed in Boyden chambers. Intracellular signalling pathways were evaluated using phosphorylation-specific antibodies or by transfection of a reporter plasmid. Results: Transcripts for the chemokine receptors CCR5 and CXCR4, which bind gp120, were detectable in human HSCs. Upon exposure to M-tropic recombinant gp120, which binds CCR5, a significant increase in HSC chemotaxis was observed (1.6±0.3-fold, p=0.03). The effects of gp120 were prevented by protein inactivation. gp120 also resulted in a significant increase in secretion (1.5±0.3-fold, p=0.03) and gene expression (1.47±0.13-fold, p=0.02) of the proinflammatory chemokine monocyte chemoattractant protein-1, and in increased gene expression of tissue inhibitor of metalloprotease-1 and interleukin-6 (2.03±0.57-fold, p=0.02). gp120-induced migration required Akt activation. gp120 also induced activation of nuclear factor-κB (NF-κB) and p38MAPK. Preincubation of HSCs with TAK779, a CCR5 receptor antagonist, prevented gp120-mediated chemotaxis and monocyte chemoattractant protein-1 secretion. Expression of CCR5 was detectable in areas of inflammation and fibrogenesis in liver biopsies of patients with HCV/HIV co-infection. Conclusions: This study shows that HIV gp120 modulates different aspects of HSC biology, including directional cell movement and expression of proinflammatory cytokines. These results identify a direct pathway possibly linking HIV infection with liver fibrogenesis via envelope proteins.",
author = "Raffaele Bruno and Sara Galastri and Paolo Sacchi and Serena Cima and Alessandra Caligiuri and Raffaella DeFranco and Stefano Milani and Sandra Gessani and Laura Fantuzzi and Francesco Liotta and Francesca Frosali and Giorgio Antonucci and Massimo Pinzani and Fabio Marra",
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AU - Bruno, Raffaele

AU - Galastri, Sara

AU - Sacchi, Paolo

AU - Cima, Serena

AU - Caligiuri, Alessandra

AU - DeFranco, Raffaella

AU - Milani, Stefano

AU - Gessani, Sandra

AU - Fantuzzi, Laura

AU - Liotta, Francesco

AU - Frosali, Francesca

AU - Antonucci, Giorgio

AU - Pinzani, Massimo

AU - Marra, Fabio

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N2 - Objective: In patients with hepatitis C virus (HCV)/HIV coinfection, a faster progression of liver fibrosis to cirrhosis has been reported. In this study, an investigation was carried out to determine whether gp120, an HIV envelope protein, modulates the biology of human hepatic stellate cells (HSCs), key cell types in the pathogenesis of fibrosis. Methods: Myofibroblastic HSCs were isolated from normal human liver tissue. Gene expression was measured by real-time PCR. Cell migration was assessed in Boyden chambers. Intracellular signalling pathways were evaluated using phosphorylation-specific antibodies or by transfection of a reporter plasmid. Results: Transcripts for the chemokine receptors CCR5 and CXCR4, which bind gp120, were detectable in human HSCs. Upon exposure to M-tropic recombinant gp120, which binds CCR5, a significant increase in HSC chemotaxis was observed (1.6±0.3-fold, p=0.03). The effects of gp120 were prevented by protein inactivation. gp120 also resulted in a significant increase in secretion (1.5±0.3-fold, p=0.03) and gene expression (1.47±0.13-fold, p=0.02) of the proinflammatory chemokine monocyte chemoattractant protein-1, and in increased gene expression of tissue inhibitor of metalloprotease-1 and interleukin-6 (2.03±0.57-fold, p=0.02). gp120-induced migration required Akt activation. gp120 also induced activation of nuclear factor-κB (NF-κB) and p38MAPK. Preincubation of HSCs with TAK779, a CCR5 receptor antagonist, prevented gp120-mediated chemotaxis and monocyte chemoattractant protein-1 secretion. Expression of CCR5 was detectable in areas of inflammation and fibrogenesis in liver biopsies of patients with HCV/HIV co-infection. Conclusions: This study shows that HIV gp120 modulates different aspects of HSC biology, including directional cell movement and expression of proinflammatory cytokines. These results identify a direct pathway possibly linking HIV infection with liver fibrogenesis via envelope proteins.

AB - Objective: In patients with hepatitis C virus (HCV)/HIV coinfection, a faster progression of liver fibrosis to cirrhosis has been reported. In this study, an investigation was carried out to determine whether gp120, an HIV envelope protein, modulates the biology of human hepatic stellate cells (HSCs), key cell types in the pathogenesis of fibrosis. Methods: Myofibroblastic HSCs were isolated from normal human liver tissue. Gene expression was measured by real-time PCR. Cell migration was assessed in Boyden chambers. Intracellular signalling pathways were evaluated using phosphorylation-specific antibodies or by transfection of a reporter plasmid. Results: Transcripts for the chemokine receptors CCR5 and CXCR4, which bind gp120, were detectable in human HSCs. Upon exposure to M-tropic recombinant gp120, which binds CCR5, a significant increase in HSC chemotaxis was observed (1.6±0.3-fold, p=0.03). The effects of gp120 were prevented by protein inactivation. gp120 also resulted in a significant increase in secretion (1.5±0.3-fold, p=0.03) and gene expression (1.47±0.13-fold, p=0.02) of the proinflammatory chemokine monocyte chemoattractant protein-1, and in increased gene expression of tissue inhibitor of metalloprotease-1 and interleukin-6 (2.03±0.57-fold, p=0.02). gp120-induced migration required Akt activation. gp120 also induced activation of nuclear factor-κB (NF-κB) and p38MAPK. Preincubation of HSCs with TAK779, a CCR5 receptor antagonist, prevented gp120-mediated chemotaxis and monocyte chemoattractant protein-1 secretion. Expression of CCR5 was detectable in areas of inflammation and fibrogenesis in liver biopsies of patients with HCV/HIV co-infection. Conclusions: This study shows that HIV gp120 modulates different aspects of HSC biology, including directional cell movement and expression of proinflammatory cytokines. These results identify a direct pathway possibly linking HIV infection with liver fibrogenesis via envelope proteins.

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