Primary infection of mice with high titer inoculum respiratory syncytial virus: characterization and response to antiviral therapy

Bolger, Gordon T.; Lapeyre, Nicole; Dansereau, Nathalie; Lagacé, Lisette; Berry, Gerald J.; Klosowski, Katy; Mewhort, Tracy; Liuzzi, Michel

doi:10.1139/y05-007

Cited by 14 publications

(12 citation statements)

References 71 publications

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“…In contrast, topically applied ribavirin was ineffective at reducing viral lung titers. This lack of efficacy correlates with previous observations that a reduction of lung viral titers in mice by ribavirin is dependent on the amount of viral inoculum employed (7). That is, the higher the inoculum is, the greater the reduction of lung viral titers at a given dose of drug.…”

Section: Lead Optimization and Antiviral Activitysupporting

confidence: 86%

Inhibitors of Respiratory Syncytial Virus Replication Target Cotranscriptional mRNA Guanylylation by Viral RNA-Dependent RNA Polymerase

Liuzzi¹,

Mason²,

Cartier³

et al. 2005

J Virol

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119

106

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Respiratory syncytial virus (RSV) is a major cause of respiratory illness in infants, immunocompromised patients, and the elderly. New antiviral agents would be important tools in the treatment of acute RSV disease. RSV encodes its own RNA-dependent RNA polymerase that is responsible for the synthesis of both genomic RNA and subgenomic mRNAs. The viral polymerase also cotranscriptionally caps and polyadenylates the RSV mRNAs at their 5 and 3 ends, respectively. We have previously reported the discovery of the first nonnucleoside transcriptase inhibitor of RSV polymerase through high-throughput screening. Here we report the design of inhibitors that have improved potency both in vitro and in antiviral assays and that also exhibit activity in a mouse model of RSV infection. We have isolated virus with reduced susceptibility to this class of inhibitors. The mutations conferring resistance mapped to a novel motif within the RSV L gene, which encodes the catalytic subunit of RSV polymerase. This motif is distinct from the catalytic region of the L protein and bears some similarity to the nucleotide binding domain within nucleoside diphosphate kinases. These findings lead to the hypothesis that this class of inhibitors may block synthesis of RSV mRNAs by inhibiting guanylylation of viral transcripts. We show that short transcripts produced in the presence of inhibitor in vitro do not contain a 5 cap but, instead, are triphosphorylated, confirming this hypothesis. These inhibitors constitute useful tools for elucidating the molecular mechanism of RSV capping and represent valid leads for the development of novel anti-RSV therapeutics.

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Section: Lead Optimization and Antiviral Activitysupporting

confidence: 86%

Inhibitors of Respiratory Syncytial Virus Replication Target Cotranscriptional mRNA Guanylylation by Viral RNA-Dependent RNA Polymerase

Liuzzi¹,

Mason²,

Cartier³

et al. 2005

J Virol

Self Cite

119

106

View full text Add to dashboard Cite

show abstract

“…The mouse model of RSV infection mimics virus infection in humans, as infected mice can develop disease states resembling pneumonia 24, 25; in addition, mice induce a robust antiviral response characterized by production of IFN-β and expression of IFN-dependent genes like Mx during early RSV infection (within 12h post-infection) 24, 25, 26, 27, 28, 29, 30. Moreover, RSV is sensitive to IFN in infected mice because as low as 200 units per ml of IFN inhibits RSV infection in mice by 100 fold 26.…”

Section: Resultsmentioning

confidence: 99%

Activation of innate immune antiviral responses by Nod2

et al. 2009

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Pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) and RIG like helicase (RLH) receptors are involved in innate immune antiviral responses. Here we show that nucleotide-binding oligomerization domain 2 (NOD2) can also function as a cytoplasmic viral PRR by triggering activation of interferon regulatory factor-3 (IRF3) and production of interferon-β (IFN). Following recognition of viral ssRNA genome, NOD2 utilized the adaptor protein MAVS (mitochondrial antiviral signaling) to activate IRF3. NOD2-deficient mice failed to produce IFN efficiently and exhibited enhanced susceptibility to virus-induced pathogenesis. Thus, the function of NOD2 as a viral PRR highlights the important role of NOD2 in host antiviral defense mechanisms.

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“…The drug was well tolerated, and prevented weight loss characteristic of RSV infection in mice [23]. In these studies, optimal recovery of body weight was seen even after single drug administration ( fig.…”

Section: Discussionmentioning

confidence: 75%

Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model

Olszewska¹,

Ispas²,

Schnoeller³

et al. 2010

Eur Respir J

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Respiratory syncytial virus (RSV) causes bronchiolitis in young children and common colds in adults. There is no licensed vaccine, and prophylactic treatment with palivizumab is very expensive and limited to high-risk infants. Ribavirin is used as an antiviral treatment in infants and immunosuppressed patients, and its use is limited due to side-effects, toxicity to the recipient and staff, and evidence of marginal clinical efficacy. Therefore, we studied the in vivo kinetics, and the antiviral and protective properties of a novel candidate for RSV disease treatment.The drug is a small molecule (TMC353121) discovered by screening for fusion inhibitory properties against RSV in a cellular infection model. The pharmacokinetics of TMC353121 was studied in BALB/c mice and antiviral effects determined by testing viral loads in lung tissue by quantitative RT-PCR and plaque assay after intranasal RSV infection.At doses of 0.25-10 mg?kg -1 , TMC353121 significantly reduced viral load, bronchoalveolar lavage cell accumulation and the severity of lung histopathological change after infection. Treatment remained effective if started within 48 h of infection, but was ineffective thereafter. Therefore, TMC353121 is a novel potent antiviral drug, in vivo reducing RSV replication and inhibiting consequential lung inflammation, with a great potential for further clinical development.

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Primary infection of mice with high titer inoculum respiratory syncytial virus: characterization and response to antiviral therapy

Cited by 14 publications

References 71 publications

Inhibitors of Respiratory Syncytial Virus Replication Target Cotranscriptional mRNA Guanylylation by Viral RNA-Dependent RNA Polymerase

Inhibitors of Respiratory Syncytial Virus Replication Target Cotranscriptional mRNA Guanylylation by Viral RNA-Dependent RNA Polymerase

Activation of innate immune antiviral responses by Nod2

Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model

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