title: The expression of HIV-1 Vpu in monocytes causes increased secretion of TGF-β that activates profibrogenic genes in hepatic stellate cells.
abstract: There is faster progression to fibrosis in persons with liver injury who are also infected with HIV. Other reports have suggested that HIV can directly infect and activate stellate cells, and the viral Tat and gp160 proteins also induce profibrogenic factors from peripheral blood mononuclear cells (PBMCs). We tested the role of HIV-1 Vpu accessory protein in promoting profibrogenic activation of hepatic stellate cells. Human stellate LX2 cells were cocultured with human monocytic U937 cells stably expressing the Vpu protein or latently infected U1 cells knocked down for Vpu expression, LX2 cells were also cultured with the supernatants from these cells. The expression of profibrogenic markers was evaluated in LX2 cells usingquantitative reverse transcription polymerase chain reaction (qRT-PCR),western blotting, immunofluorescence,flow cytometry and ELISA were used to confirm and quantitate protein expression. Monocytic cells expressing Vpu increased the expression of profibrogenic markers in LX2 cells. The culture supernatants of these cells contained increased levels of transforming growth factor beta (TGF-β), which correlated with increased activity of the AP-1 transcription factor. Antibodies against TGF-β or a TGF-β receptor inhibitor (SB431452) reversed Vpu-mediated profibrogenic activation of LX2 cells, suggesting that TGF-β mediated these effects. The cytokine macrophage migration inhibitory factor (MIF) attenuated Vpu-mediated TGF-β secretion and profibrogenic effects on LX2 cells. Besides its other roles in pathogenesis, Vpu is likely to contribute to hepatic fibrosis through this hitherto unknown mechanism.
authors.affiliation: Virology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
authors.forename: Paresh
authors.initials: P
authors.lastname: Patel
authors.affiliation: Virology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
authors.forename: Nabab
authors.initials: N
authors.lastname: Khan
authors.affiliation: Virology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
authors.forename: Manjusha
authors.initials: M
authors.lastname: Rani
authors.affiliation: Virology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
authors.forename: Deepti
authors.initials: D
authors.lastname: Gupta
authors.affiliation: Virology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
authors.forename: Shahid
authors.initials: S
authors.lastname: Jameel
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D018920:Coculture Techniques; D005355:Fibrosis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism*; D054298:Human Immunodeficiency Virus Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism*; D019076:Transgenes; D054334:Viral Regulatory and Accessory Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D015415:Biomarkers; D054298:Human Immunodeficiency Virus Proteins; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins; C515598:MIF protein, human