New Antiviral Pathway That Mediates Hepatitis C Virus Replicon Interferon Sensitivity through ADAR1

CBER/FDA, HFM-448, 8800 Rockville Pike, Bethesda, MD 20892, USA.
Journal of Virology (Impact Factor: 4.44). 06/2005; 79(10):6291-8. DOI: 10.1128/JVI.79.10.6291-6298.2005
Source: PubMed


While many clinical hepatitis C virus (HCV) infections are resistant to alpha interferon (IFN-α) therapy, subgenomic in vitro
self-replicating HCV RNAs (HCV replicons) are characterized by marked IFN-α sensitivity. IFN-α treatment of replicon-containing
cells results in a rapid loss of viral RNA via translation inhibition through double-stranded RNA-activated protein kinase
(PKR) and also through a new pathway involving RNA editing by an adenosine deaminase that acts on double-stranded RNA (ADAR1).
More than 200 genes are induced by IFN-α, and yet only a few are attributed with an antiviral role. We show that inhibition
of both PKR and ADAR1 by the addition of adenovirus-associated RNA stimulates replicon expression and reduces the amount of
inosine recovered from RNA in replicon cells. Small inhibitory RNA, specific for ADAR1, stimulated the replicon 40-fold, indicating
that ADAR1 has a role in limiting replication of the viral RNA. This is the first report of ADAR's involvement in a potent
antiviral pathway and its action to specifically eliminate HCV RNA through adenosine to inosine editing. These results may
explain successful HCV replicon clearance by IFN-α in vitro and may provide a promising new therapeutic strategy for HCV as
well as other viral infections.

Download full-text


Available from: Montserrat Puig, Dec 19, 2014
  • Source
    • "Subsequent studies demonstrated that ADAR1 acts as a proviral host factor in the context of MeV infection (Toth et al., 2009). In contrast, ADAR has an antiviral function in other virus infections (Samuel, 2011; Taylor et al., 2005). Future research needs to elucidate the roll of ADAR in HMPV pathogenesis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Type I interferon (IFN) production is one of the hallmarks of host innate immune responses upon virus infection. While most respiratory viruses carry IFN-antagonists, reports on human Metapneumovirus (HMPV) have been conflicting. Using deep sequencing we demonstrate that HMPV particles accumulate excessive amounts of defective interfering RNA (DIs) rapidly upon in-vitro passage, which are associated with IFN induction. Importantly, the DIs were edited extensively; up to 70% of the original A and T residues had mutated to G or C respectively. Such high editing rates of viral RNA have not been reported before. Bioinformatics and PCR assays indicated that Adenosine Deaminase acting on RNA (ADAR) is the most likely editing enzyme. HMPV thus has an unusually high propensity to generate DIs, which are edited at an unprecedented high frequency. The conflicting published data on HMPV IFN induction and antagonism are likely explained by DIs in virus stocks. The interaction of HMPV DIs with the RNA editing machinery and IFN responses warrants further investigation.
    Journal of General Virology 04/2014; 95(Pt 8). DOI:10.1099/vir.0.066100-0 · 3.18 Impact Factor
  • Source
    • "Among others, an increased expression has been described for the 2′-5′-oligoadenylate synthase 1 (OAS1)/RNAse L system, which degrades viral and cellular RNA [73], and the RNA-specific adenosine deaminase acting on RNA 1 (ADAR1), which converts adenosine residues into inosine residues in dsRNA [74], thereby mutating and destabilizing secondary viral RNA structures [75]. Similarly, induction of other ISGs, such as P56 [76] and protein kinase R (PKR) [77], which inhibit translation of viral and host RNAs [78], has been reported. "
    [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACT: Hepatitis C virus (HCV) induces a chronic infection in more than two-thirds of HCV infected subjects. The inefficient innate and adaptive immune responses have been shown to play a major pathogenetic role in the development and persistence of HCV chronic infection. Several aspects of the interactions between the virus and the host immune system have been clarified and, in particular, mechanisms have been identified which underlie the ability of HCV to seize and subvert innate as well as adaptive immune responses. The present review summarizes recent findings on the interaction between HCV infection and innate immune response whose final effect is the downstream inefficient development of antigen-specific adaptive immunity, thereby contributing to virus persistence.
    Infectious Agents and Cancer 03/2012; 7(1):7. DOI:10.1186/1750-9378-7-7 · 2.36 Impact Factor
  • Source
    • "ADAR1 was also known to edit double-stranded RNA found in the measles virus, which inhibited virus assembly and release from cells, leading to a persistent infection and development of fatal neuropathic measles infection (Horikami and Moyer, 1995). Taylor, et al. (2005) showed that ADAR1-induced viral RNA editing inhibited Hepatitis C viral replication (Taylor et al., 2005). Recently Suspene et al. (Suspene et al.) have shown ADAR1 induced mutation in seasonal influenza and attenuated measles viruses. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We examined the antiviral activity of ADAR1 against HIV-1. Our results indicated that ADAR1 in a transfection system inhibited production of viral proteins and infectious HIV-1 in various cell lines including 293T, HeLa, Jurkat T and primary CD4+ T cells, and was active against a number of X4 and R5 HIV-1 of different clades. Further analysis showed that ADAR1 inhibited viral protein synthesis without any effect on viral RNA synthesis. Mutational analysis showed that ADAR1 introduced most of the A-to-G mutations in the rev RNA, in the region of RNA encoding for Rev Response Element (RRE) binding domain and in env RNA. These mutations inhibited the binding of rev to the RRE and inhibited transport of primary transcripts like gag, pol and env from nucleus to cytoplasm resulting in inhibition of viral protein synthesis without any effect on viral RNA synthesis. Furthermore, ADAR1 induced mutations in the env gene inhibited viral infectivity.
    Virology 11/2011; 422(2):265-77. DOI:10.1016/j.virol.2011.10.024 · 3.32 Impact Factor
Show more