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.