title: Liver Fibrosis in HCV Monoinfected and HIV/HCV Coinfected Patients: Dysregulation of Matrix Metalloproteinases (MMPs) and Their Tissue Inhibitors TIMPs and Effect of HCV Protease Inhibitors.
abstract: An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may contribute to liver fibrosis in patients with hepatitis C (HCV) infection. We measured the circulating levels of different MMPs and TIMPs in HCV monoinfected and HIV/HCV coinfected patients and evaluated the potential for anti-HCV therapy to modulate MMP and TIMP levels in HCV subjects. We analyzed 83 plasma samples from 16 HCV monoinfected patients undergoing dual or triple anti-HCV therapy, 15 HIV/HCV coinfected patients with undetectable HIV load, and 10 healthy donors (HD). Levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, TIMP-1, and TIMP-2 were measured by a SearchLight Multiplex Immunoassay Kit. MMP-2 and MMP-9 were the highest expressed MMPs among all the analyzed samples and their levels significantly increased in HCV monoinfected and HIV/HCV coinfected subjects compared to HD. TIMP-1 levels were significantly higher in HCV and HIV/HCV subjects compared to HD and were correlated with liver stiffness. These findings raise the possibility of using circulating TIMP-1 as a non-invasive marker of liver fibrosis in HCV infection. A longitudinal study demonstrated that MMP-9 levels significantly decreased (40% reduction from baseline) in patients receiving dual as well as triple direct-acting antivirals (DAA) anti-HCV therapy, which had no effect on MMP-2, TIMP-1, and TIMP-2. As the dysregulation of MMP-2 and MMP-9 may reflect inflammatory processes in the liver, the decrease of MMP-9 following HCV protease inhibitor treatment suggests a positive effect on the reduction of liver inflammation.
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, Aldo Moro University, Bari 70126, Italy. tiziana.latronico@uniba.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Latronico
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome 00185, Italy. claumascia@tiscali.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mascia
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, Aldo Moro University, Bari 70126, Italy. ilaria.pati@hotmail.it.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Pati
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome 00185, Italy. paola.zuccala@libero.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Zuccala
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome 00185, Italy. fabio.mengoni@uniroma1.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Mengoni
authors.affiliation: Infectious Diseases Unit, Sapienza University, Polo Pontino, Latina 04100, Italy. raffa.marocco@libero.it.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Marocco
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome 00185, Italy. tizianatieghi@libero.it.|Infectious Diseases Unit, Sapienza University, Polo Pontino, Latina 04100, Italy. tizianatieghi@libero.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Tieghi
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome 00185, Italy. valeria.belvisi@gmail.com.|Infectious Diseases Unit, Sapienza University, Polo Pontino, Latina 04100, Italy. valeria.belvisi@gmail.com.
authors.forename: Valeria
authors.initials: V
authors.lastname: Belvisi
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome 00185, Italy. miriam.lichtner@uniroma1.it.|Infectious Diseases Unit, Sapienza University, Polo Pontino, Latina 04100, Italy. miriam.lichtner@uniroma1.it.
authors.forename: Miriam
authors.initials: M
authors.lastname: Lichtner
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome 00185, Italy. vincenzo.vullo@uniroma1.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Vullo
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome 00185, Italy. claudio.mastroianni@uniroma1.it.|Infectious Diseases Unit, Sapienza University, Polo Pontino, Latina 04100, Italy. claudio.mastroianni@uniroma1.it.
authors.forename: Claudio Maria
authors.initials: CM
authors.lastname: Mastroianni
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, Aldo Moro University, Bari 70126, Italy. graziamaria.liuzzi@uniba.it.
authors.forename: Grazia Maria
authors.initials: GM
authors.lastname: Liuzzi
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000150:complications*; D006526:Hepatitis C / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007118:Immunoassay; D008103:Liver Cirrhosis / Q000150:complications / Q000473:pathology*; D008137:Longitudinal Studies; D008297:Male; D020782:Matrix Metalloproteinases / Q000097:blood* / Q000378:metabolism; D008875:Middle Aged; D011480:Protease Inhibitors / Q000627:therapeutic use*; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases
keywords: HIV/HCV coinfection; anti-HCV therapy; liver fibrosis; matrix metalloproteinases; tissue inhibitors of metalloproteinases