Enhanced antiviral effect in cell culture of type 1 interferon and ribozymes targeting HCV RNA.
We have recently shown that the replication of an HCV-poliovirus (PV) chimera that is dependent upon the hepatitis C virus (HCV) 5' untranslated region (UTR) can be inhibited by treatment with ribozymes targeting HCV RNA. To determine the antiviral effects of anti-HCV ribozyme treatment in combination with type 1 interferon (IFN), we analysed the replication of this HCV-PV chimera in HeLa cells treated with anti-HCV ribozyme and/or IFN-alpha2a, IFN-alpha2b, or consensus IFN. The anti-HCV ribozyme, or any of the IFNs alone have significant inhibitory effects on HCV-PV replication compared to control treatment (> or = 85%, P < 0.01). The maximal inhibition due to IFN treatment (94%, P < 0.01) was achieved with > or = 50 U/ml for either IFN-alpha2a or IFN-alpha2b compared to control treatment. A similar level of inhibition in viral replication could be achieved with a 5-fold lower dose of IFN if ribozyme targeting the HCV 5' UTR was given in combination. For consensus IFN, the dose could be reduced by > 12.5-fold if ribozyme targeting the HCV 5' UTR was given in combination. Conversely, the dose of ribozyme could be reduced 3-fold if given in combination with any of the IFN preparations. Moreover, treatment with low doses (1-25 U/mL) of IFN-alpha2a, IFN-alpha2b, or consensus IFN in combination with anti-HCV ribozyme resulted in > 98% inhibition of HCV-PV replication compared to control treatment (P < 0.01). These results demonstrate that IFN and ribozyme each have a beneficial antiviral effect that is augmented when given in combination.
Macejak
D G
DG
Ribozyme Pharmaceuticals Inc., Boulder, Colorado 80301, USA.
Jensen
K L
KL
Pavco
P A
PA
Phipps
K M
KM
Heinz
B A
BA
Colacino
J M
JM
Blatt
L M
LM
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006367:HeLa Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D017955:Poliovirus / Q000235:genetics; D016337:RNA, Catalytic / Q000138:chemical synthesis / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics*; D011994:Recombinant Proteins; D014162:Transfection; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D016337:RNA, Catalytic; D012367:RNA, Viral; D011994:Recombinant Proteins