Ribavirin and interferon alter MMP-9 abundance in vitro and in HIV-HCV-coinfected patients

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 coinfectcd patient cohort. Methods: THP-1 and LX-2 cells were treated with ribavirin (RBV)/interferon-alpha (IFN-alpha) 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-alpha. Samples were subjected to gelatin zymography, real-time RT-PCR and/or ELISA, where appropriate. Results: RBV/IFN-alpha 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-alpha, 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-alpha decreased plasma MMP-9 abundance in HIV-HCV patients. Conclusions: These data demonstrate that RBV/pegylated IFN-alpha 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.