The HIV Envelope Protein GP120 Modulates The Biology of Human Hepatic Stellate Cells: A Link Between HIV Infection and Liver Fibrogenesis

Raffaele Bruno ¹, Sara Galastri ², Paolo Sacchi ¹, Serena Cima ¹, Alessandra Caligiuri ², Raffaella DeFranco ², Stefano Milani ³, Sandra Gessani ⁴, Laura Fantuzzi ⁴, Francesco Liotta ⁵, Francesca Frosali ⁵, Giorgio Antonucci ⁶, Massimo Pinzani ² and Fabio Marra ^2*

¹ Division Infectious and Tropical Diseases, University of Pavia-Foundation IRCCS San Matteo Hospital, Italy
² Dipartimento di Medicina Interna, University of Florence, Italy
³ Center for Research, Transfer and Higher Education Deno THE University of Florence, Italy
⁴ Istituto Superiore di Sanità, Rome, Italy
⁵ Dipartimento di Medicina Interna, Italy
⁶ INMI L. Spallanzani - IRCCS, Rome, Italy

^* To whom correspondence should be addressed. E-mail: f.marra{at}dmi.unifi.it.

Accepted 7 August 2009

Abstract

Objective: In patients with HCV/HIV co-infection, a faster progression of liver fibrosis to cirrhosis has been reported. In this study we investigated whether gp120, a HIV envelope protein, modulates the biology of human hepatic stellate cells (HSC), key cell types in the pathogenesis of fibrosis.

Methods: Myofibroblastic HSC 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 HSC. 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 pro-inflammatory chemokine MCP-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 NF-B and p38MAPK. Preincubation of HSC with TAK779, a CCR5 receptor antagonist, prevented gp120-mediated chemotaxis and MCP-1 secretion. Expression of CCR5 was detectable in areas of inflammation and fibrogenesis in liver biopsies of patients with HCV/HIV coinfection.

Conclusions: This study shows that HIV-gp120 modulates different aspects of HSC biology, including directional cell movement and expression of pro-inflammatory cytokines. These results identify a direct pathway possibly linking HIV infection with liver fibrogenesis via envelope proteins.