Hijacking hepatitis C viral replication with a non-coding replicative RNA.
The current treatments used against RNA viruses have a limited efficacy and are often hampered by the induction of side-effects. The specific delivery of antiviral proteins in infected cells should increase their efficiency and reduce their impact on healthy cells. Here, we describe the development of a new approach which takes advantage of the viral replication machinery to specifically target the antiviral protein expression to the infected cells. The strategy is based on the delivery of a non-coding (-)RNA carrying the structures required for the binding of the viral replication complex and the complementary sequence of an antiviral gene. The viral replication complex replicates the (-)RNA similarly to the viral genome to give a coding (+)RNA from which the antiviral protein will be expressed. As non-infected cells do not express the replication complex, this specific machinery can be used to target virus-infected cells without affecting healthy cells. We show that this approach can be successfully applied to the hepatitis C virus. In both replicon-harboring cells (genotype 1b) and JFH-1 infected cells (genotype 2a), nrRNAs induced a strong decrease in genomic RNA and viral protein NS5A. These effects were correlated with a strong activation of several interferon-stimulating genes.
Bitard
Juliette
J
UMR CNRS, IFR, Université Victor Segalen Bordeaux, France.
Chognard
Gaëlle
G
Dumas
Estelle
E
Rumi
Julie
J
Masante
Cyril
C
Mahias
Kathleen
K
Astier-Gin
Thérèse
T
Ventura
Michel
M
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D022661:RNA, Untranslated / Q000494:pharmacology*; D012367:RNA, Viral / Q000096:biosynthesis; D017361:Viral Nonstructural Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D022661:RNA, Untranslated; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase