The interferon stimulated gene 15 functions as a proviral factor for the hepatitis C virus and as a regulator of the IFN response.
BACKGROUND
Non-response to combination therapy by patients with hepatitis C virus (HCV) has previously been associated with a strong hepatic upregulation of interferon stimulated genes (ISGs) including ISG15. Therefore, the aim of this study was to further elucidate the functional role of this molecule.


METHODS
ISG15 expression was suppressed by siRNAs or enhanced by over-expression in genomic and subgenomic human or murine HCV replicon systems. In addition, ISG15 expression was analysed in liver samples of patients with HCV prior to antiviral therapy and correlated with clinical and virological parameters.


RESULTS
Short- or long-term knockdown of ISG15 expression suppressed HCV replication comparable to IFNs without evidence for the induction of resistant mutations. Triple therapy consisting of ISG15 knockdown, interferon alpha (IFNalpha) and ribavirin led to complete suppression of the HCV NS5A protein, corresponding to 99% suppression of HCV-RNA compared to 75% suppression by IFNalpha and ribavirin only. Combination treatment of ISG15 knockdown and IFN was associated with enhanced and prolonged expression of selected ISGs. Consistent with these in vitro data, high hepatic ISG15 levels correlated with the unfavourable HCV genotype 1, a high hepatic HCV load and a low antiviral response to IFN during the initial phase of treatment.


CONCLUSIONS
ISG15 plays an important role in the HCV replication cycle. Therefore, therapies based on the suppression of ISG15 may provide a promising strategy to overcome non-response to standard combination treatment in the future. Furthermore, analysis of ISG15 prior to therapy may be useful to predict short-term and long-term outcome and thus tailor antiviral therapy with pegIFN and ribavirin.
Broering
Ruth
R
Department of Gastroenterology and Hepatology, University Hospital of Essen, Hufelandstr 55, Essen 45122, Germany.
Zhang
Xiaozhen
X
Kottilil
Shyam
S
Trippler
Martin
M
Jiang
Min
M
Lu
Mengji
M
Gerken
Guido
G
Schlaak
Joerg F
JF
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000502:physiology*; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000378:metabolism / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000821:virology; D008113:Liver Neoplasms / Q000378:metabolism; D051379:Mice; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics; D012093:Replicon; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use; D014452:Ubiquitins / Q000097:blood / Q000235:genetics / Q000502:physiology*; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics / Q000502:physiology
D000998:Antiviral Agents; D016207:Cytokines; D016898:Interferon-alpha; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D014452:Ubiquitins; D012254:Ribavirin; C074034:ISG15 protein, human