title: Ribavirin and interferon alter MMP-9 abundance in vitro and in HIV-HCV-coinfected patients.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) are central to tissue remodelling during HIV-HCV infection. Here, we assess the potential for antiviral therapy to modulate MMP abundance in THP-1 monocyte/macrophages and LX-2 hepatic stellate cells, and in a coinfected patient cohort.
  
  
  METHODS
  THP-1 and LX-2 cells were treated with ribavirin (RBV)/interferon-α (IFN-α) and select HIV antivirals. Venous blood was reserved from HIV-HCV-coinfected patients, HIV- and HCV-monoinfected patients, and healthy controls, with the HIV-HCV cohort being sampled again at day 3 and 14 subsequent to the start of combination therapy with RBV/pegylated IFN-α. Samples were subjected to gelatin zymography, real-time RT-PCR and/or ELISA, where appropriate.
  
  
  RESULTS
  RBV/IFN-α decreased MMP-9 activity, and increased MMP-9 mRNA and protein expression in THP-1 cells, but not in LX-2 cells. Decreases in MMP-9 activity were mediated by IFN-α, which also attenuated RBV induction of MMP-9 activity and protein expression in THP-1 cells. Saquinavir and lopinavir, HIV protease inhibitors, reduced MMP-9 activity in THP-1 and LX-2 cells, respectively. Plasma MMP-9 activity and expression was higher in HIV-HCV and HIV patients compared with HCV patients and healthy controls. MMP-2 and TIMP-2 levels were similar in all groups. RBV/pegylated IFN-α decreased plasma MMP-9 abundance in HIV-HCV patients.
  
  
  CONCLUSIONS
  These data demonstrate that RBV/pegylated IFN-α reduce plasma MMP-9 abundance in vivo and may reduce its activity in vitro through immune cells, such as monocyte/macrophages, rather than hepatic stellate cells. The results of this study indicate that such therapy may mediate tissue remodelling associated with HIV-HCV coinfection through effects on MMP-9.
authors.affiliation: Department of Pharmacology and Therapeutics, Trinity College Dublin, Dublin, Ireland.
authors.forename: Alan
authors.initials: A
authors.lastname: Kennedy
authors.forename: Martina
authors.initials: M
authors.lastname: Hennessy
authors.forename: Colm
authors.initials: C
authors.lastname: Bergin
authors.forename: Fiona
authors.initials: F
authors.lastname: Mulcahy
authors.forename: Susan
authors.initials: S
authors.lastname: Hopkins
authors.forename: J Paul
authors.initials: JP
authors.lastname: Spiers
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002460:Cell Line; D015331:Cohort Studies; D060085:Coinfection; D005260:Female; D006678:HIV / Q000187:drug effects* / Q000502:physiology; D015658:HIV Infections / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use; D007494:Ireland; D061466:Lopinavir / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012367:RNA, Viral; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use; D019258:Saquinavir / Q000008:administration & dosage / Q000627:therapeutic use; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000097:blood; D006113:United Kingdom; D019562:Viral Load / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; D061466:Lopinavir; D012254:Ribavirin; D019258:Saquinavir