Interferon and Its Inducers—A Never-Ending Story: “Old” and “New” Data in a New Perspective

Clercq, Erik De

doi:10.1086/505351

Cited by 22 publications

(16 citation statements)

References 47 publications

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“…Although this study was based on activity against HCV, there are other viruses that can be inhibited by IFNs (5), and these TLRs may therefore represent attractive targets for a range of viral infections.…”

Section: Discussionmentioning

confidence: 99%

Investigating Toll-Like Receptor Agonists for Potential To Treat Hepatitis C Virus Infection

Thomas

Laxton

Rodman

et al. 2007

Antimicrob Agents Chemother

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Toll-like receptors (TLRs) are key mediators of innate immunity, and their activation by microbial components leads to the production of cytokines and interferons. Recombinant alpha interferon has been used to treat several viral diseases and is the current standard of care for hepatitis C virus (HCV) infection. Recently, agonists of TLR7 and TLR9 have been shown to have clinical efficacy in HCV patients, and this is correlated with their ability to induce endogenous type I interferon production. We have carried out a comprehensive study of agonists of TLRs 1 to 9 to determine if any additional TLRs can induce antiviral molecules from human peripheral blood mononuclear cells (PBMCs). The agonists were incubated with PBMCs, and the supernatant was then removed and added to HCV replicon cells to assess antiviral activity. Agonists of TLRs 3, 4, 7, 8, and 9 were found to be potent inducers of antiviral activity in PBMC supernatants, and the activity correlated with the induction of alpha interferon and the interferon-induced antiviral biomarker 2,5-oligoadenylate synthase. Antiviral activity of TLR7 and TLR8 agonists was blocked by an antibody that binds to the type I interferon receptor, confirming that the antiviral activity results from type I interferon induction. TLR4 and TLR8 agonists were found to strongly induce the proinflammatory cytokines interleukin 1␤ and tumor necrosis factor alpha at concentrations similar to those inducing antiviral activity. This raises concerns about adverse side effects if these were to be used as antiviral agents. We therefore conclude that TLRs 3, 7, and 9 represent the most attractive targets for the development of new HCV therapies.The World Health Organization reports that ϳ170 million people worldwide are infected with hepatitis C virus (HCV) (29). The disease affects primarily the liver, with 10 to 20% of chronic infections leading to cirrhosis and 1 to 5% leading to liver cancer. The recommended standard therapy for HCV is a once-weekly injection of pegylated interferon alpha 2a (IFN␣2a) plus daily oral ribavirin. The sustained viral response is approximately 50% (23), and the therapy is associated with significant side effects including flu-like symptoms, depression, and injection site reactions (9). In addition, some patients develop neutralizing antibodies to recombinant IFN, which may contribute to treatment failures (2, 13). There is therefore a need to discover new drugs with improved efficacy and reduced side effects.Toll-like receptors (TLRs) are a family of receptors that play a key role in innate immunity. On binding microbial ligands, they induce a signaling cascade resulting in the induction of type I IFNs and other cytokines, which drive an inflammatory response and activate the adaptive immune system (for a review, see reference 27). Whereas current IFN therapy involves the administration of a single IFN-␣ subtype (2a or 2b), TLR activation induces a range of different IFN subtypes. For example, the TLR7 agonist imiquimod has been shown to induce IFN-␣1, -␣2...

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Section: Discussionmentioning

confidence: 99%

Investigating Toll-Like Receptor Agonists for Potential To Treat Hepatitis C Virus Infection

Thomas

Laxton

Rodman

et al. 2007

Antimicrob Agents Chemother

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“…Treatment of mice with the immune-stimulating agent poly(I:C), a synthetic dsRNA, is known to protect from severe virus infections (20). We wanted to confirm this for the highly virulent RVFV strain ZH548, which was isolated during a 1977 epizootic in Egypt (43).…”

Section: Antiviral Effect Of Ifn and Pkr Against Rvfvmentioning

confidence: 98%

NSs Protein of Rift Valley Fever Virus Induces the Specific Degradation of the Double-Stranded RNA-Dependent Protein Kinase

Habjan

Pichlmair

Elliott

et al. 2009

J Virol

226

278

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Rift Valley fever virus (RVFV) continues to cause large outbreaks of acute febrile and often fatal illness among humans and domesticated animals in Africa, Saudi Arabia, and Yemen. The high pathogenicity of this bunyavirus is mainly due to the viral protein NSs, which was shown to prevent transcriptional induction of the antivirally active type I interferons (alpha/beta interferon [IFN-␣/␤]). Viruses lacking the NSs gene induce synthesis of IFNs and are therefore attenuated, whereas the noninducing wild-type RVFV strains can only be inhibited by pretreatment with IFN. We demonstrate here in vitro and in vivo that a substantial part of the antiviral activity of IFN against RVFV is due to a double-stranded RNA-dependent protein kinase (PKR). PKR-mediated virus inhibition, however, was much more pronounced for the strain Clone 13 with NSs deleted than for the NSs-expressing strain ZH548. In vivo, Clone 13 was nonpathogenic for wild-type (wt) mice but could regain pathogenicity if mice lacked the PKR gene. ZH548, in contrast, killed both wt and PKR knockout mice indiscriminately. ZH548 was largely resistant to the antiviral properties of PKR because RVFV NSs triggered the specific degradation of PKR via the proteasome. The NSs proteins of the related but less virulent sandfly fever Sicilian virus and La Crosse virus, in contrast, had no such anti-PKR activity despite being efficient suppressors of IFN induction. Our data suggest that RVFV NSs has gained an additional anti-IFN function that may explain the extraordinary pathogenicity of this virus.

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“…Ampligen has proven to be effective against the viruses being tested here. The antiviral mechanisms of interferons and interferon inducers has previously been reviewed (De Clercq 2006). It is recognized that the primary mechanism of action of Ampligen is via activation of Toll-like Receptor-3 (TLR-3) on cells.…”

Section: Introductionmentioning

confidence: 99%

Correlation between breakdown of the blood–brain barrier and disease outcome of viral encephalitis in mice

et al. 2007

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Changes in the permeability of the blood-brain barrier (BBB) were evaluated in two mouse models of viral encephalitis. The ability of sodium fluorescein (NaFl) to cross the BBB from the serum into the central nervous system was assayed in animals inoculated with virulent strains of either Banzi or Semliki Forest viruses. To test the hypothesis that increases in BBB permeability were associated with poor disease outcome subsequent experiments measured BBB permeability in conjunction with treatment with the interferon inducer Ampligen (poly I: poly C 12 U). A single intraperitoneal injection of Ampligen (1 mg/kg) administered either 24 h or 4-6 h before, but not 24 h after, virus inoculation with Banzi virus provided significant improvements in survival, viral brain titers, weight change, and BBB permeability. In comparison, a similar treatment with Ampligen administered either 24 h or 4-6 h before inoculation with Semliki Forest virus was able to significantly improve weight change, and BBB permeability, but only animals receiving Ampligen 4-6 h pre-virus showed a significantly improved mortality. In general, it was found that evaluation of BBB permeability was a more sensitive indicator of disease outcome and the antiviral efficacy Ampligen than either weight change or brain viral titers.

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Interferon and Its Inducers—A Never-Ending Story: “Old” and “New” Data in a New Perspective

Cited by 22 publications

References 47 publications

Investigating Toll-Like Receptor Agonists for Potential To Treat Hepatitis C Virus Infection

Investigating Toll-Like Receptor Agonists for Potential To Treat Hepatitis C Virus Infection

NSs Protein of Rift Valley Fever Virus Induces the Specific Degradation of the Double-Stranded RNA-Dependent Protein Kinase

Correlation between breakdown of the blood–brain barrier and disease outcome of viral encephalitis in mice

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