A novel immunomodulatory mechanism of ribavirin in suppressing natural killer cell function

Ogbomo, Henry; Michaelis, Martin; Altenbrandt, Behric; Cinatl, Jindrich

doi:10.1016/j.bcp.2009.07.026

Cited by 14 publications

(12 citation statements)

References 59 publications

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“…In the last years, together with the direct antiviral effects, ribavirin has been reported to have immunomodulatory effects. Ribavirin induces a switch in T-helper (Th) cell phenotype from type 2 to type 1 (13,14,15). According to our data Isoprinosine has the ability to activate the cytokine cascade from the first day of intake (3) and in this way resembles the effects of IFN like in standard bi-therapy.…”

Section: Discussionmentioning

confidence: 72%

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Could Inosine pranobex and Ribavirin in combination restore immune competence in chronic HCV advanced liver disease?

Nikolova¹,

Antonov²,

Mateva³

et al. 2014

MedInform

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The management of patients with advanced chronic HCV liver disease is still a problem. There is insufficient data about the role of immunomodulatory agents. The aim of the present study was to evaluate the benefit of prolonged co-administration of Inosine pranobex (Isoprinosine) and Ribavirin in patients with HCV advanced liver disease and to assess the dynamics of the IP-10 serum levels and thus -changes in the immune status of patients. Methods: Five patients (2 males, 3 females; median age 63), with chronic HCV genotype 1 infection were studied (with failed standard bitherapy). All patients received Ribavirin and Isoprinosine. HCVRNA was measured at baseline and at day 40, month 3, 6 and 12 during treatment. IP-10 levels -at baseline and at day 10, 20, 40, 60, month 3, 6 and 12. Results: IP-10 levels were elevated in all patients at the baseline. An increase at day 10 or 20 was found in 4/5 patients and reduction at day 40 or 60 in same 4 patients. At month 12 the levels were significantly reduced (P=0.043). There was also an initially slight increase of ALT and subsequent reduction (P=0.043). The count of platelets increased in 4/5 patients. No effect on viral load was found. Conclusion: The therapeutic regime is well tolerated, no severe adverse events were documented. An improvement of the disease severity and liver inflammation were observed, with no effect on the viral load. We found reduction of IP-10 levels at month 12 -a sign of immune competence restoration.

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Section: Discussionmentioning

confidence: 72%

“…Ribavirin induces a switch in T-helper (Th) cell phenotype from type 2 to type 1 (humoral immune responses to cell-mediated) (13,14,15). The exact mechanism is unclear.…”

Section: Introductionmentioning

confidence: 99%

Could Inosine pranobex and Ribavirin in combination restore immune competence in chronic HCV advanced liver disease?

Nikolova¹,

Antonov²,

Mateva³

et al. 2014

MedInform

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“…Glycyrrhizin concentrations up to 200 lg/ml did not influence NK cell viability (data not shown). In contrast to the antiviral drug ribavirin that had been shown before to inhibit NK cell activity [45], glycyrrhizin did not affect NK cell cytolytic activity (Fig. 4).…”

Section: Influence Of Glycyrrhizin On Natural Killer (Nk) Cell Activitymentioning

confidence: 78%

“…cell cytotoxic activity and protected mice from lethal infection [52]. Also, antiviral drugs may interfere with cytotoxic cells that control virus replication as demonstrated for ribavirin that was shown to hamper NK cell cytolytic activity [45]. Therefore, the ability of glycyrrhizin to interfere with H5N1-induced hypercytokinaemia in concentrations that do not affect NK cell activity may further favour its use as complementary additional anti-influenza treatment option.…”

Section: Discussionmentioning

confidence: 96%

Glycyrrhizin inhibits highly pathogenic H5N1 influenza A virus-induced pro-inflammatory cytokine and chemokine expression in human macrophages

Michaelis

Geiler

Naczk

et al. 2010

Med Microbiol Immunol

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Hypercytokinaemia is thought to contribute to highly pathogenic H5N1 influenza A virus disease. Glycyrrhizin is known to exert immunomodulatory and anti-inflammatory effects and therefore a candidate drug for the control of H5N1-induced pro-inflammatory gene expression. Here, the effects of an approved parenteral glycyrrhizin preparation were investigated on H5N1 virus replication, H5N1-induced pro-inflammatory responses, and H5N1-induced apoptosis in human monocyte-derived macrophages. Glycyrrhizin 100 μg/ml, a therapeutically achievable concentration, impaired H5N1-induced production of CXCL10, interleukin 6, and CCL5 and inhibited H5N1-induced apoptosis but did not interfere with H5N1 replication. Global inhibition of immune responses may result in the loss of control of virus replication by cytotoxic immune cells including natural killer cells and cytotoxic CD8(+) T-lymphocytes. Notably, glycyrrhizin concentrations that inhibited H5N1-induced pro-inflammatory gene expression did not affect cytolytic activity of natural killer cells. Since H5N1-induced hypercytokinaemia is considered to play an important role within H5N1 pathogenesis, glycyrrhizin may complement the arsenal of potential drugs for the treatment of H5N1 disease.

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“…Other modes of action may include direct inhibition of the influenza virus RdRp (31,32) and interference with capping of viral RNA (33). Some data suggest that ribavirin affects inflammatory and T-cell responses in vivo (34)(35)(36).…”

mentioning

confidence: 99%

Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs

Pauly

Lauring

2015

J Virol

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Lethal mutagenesis is a broad-spectrum antiviral strategy that exploits the high mutation rate and low mutational tolerance of many RNA viruses. This approach uses mutagenic drugs to increase viral mutation rates and burden viral populations with mutations that reduce the number of infectious progeny. We investigated the effectiveness of lethal mutagenesis as a strategy against influenza virus using three nucleoside analogs, ribavirin, 5-azacytidine, and 5-fluorouracil. All three drugs were active against a panel of seasonal H3N2 and laboratory-adapted H1N1 strains. We found that each drug increased the frequency of mutations in influenza virus populations and decreased the virus' specific infectivity, indicating a mutagenic mode of action. We were able to drive viral populations to extinction by passaging influenza virus in the presence of each drug, indicating that complete lethal mutagenesis of influenza virus populations can be achieved when a sufficient mutational burden is applied. Population-wide resistance to these mutagenic agents did not arise after serial passage of influenza virus populations in sublethal concentrations of drug. Sequencing of these drug-passaged viral populations revealed genome-wide accumulation of mutations at low frequency. The replicative capacity of drug-passaged populations was reduced at higher multiplicities of infection, suggesting the presence of defective interfering particles and a possible barrier to the evolution of resistance. Together, our data suggest that lethal mutagenesis may be a particularly effective therapeutic approach with a high genetic barrier to resistance for influenza virus. IMPORTANCEInfluenza virus is an RNA virus that causes significant morbidity and mortality during annual epidemics. Novel therapies for RNA viruses are needed due to the ease with which these viruses evolve resistance to existing therapeutics. Lethal mutagenesis is a broad-spectrum strategy that exploits the high mutation rate and the low mutational tolerance of most RNA viruses. It is thought to possess a higher barrier to resistance than conventional antiviral strategies. We investigated the effectiveness of lethal mutagenesis against influenza virus using three different drugs. We showed that influenza virus was sensitive to lethal mutagenesis by demonstrating that all three drugs induced mutations and led to an increase in the generation of defective viral particles. We also found that it may be difficult for resistance to these drugs to arise at a population-wide level. Our data suggest that lethal mutagenesis may be an attractive anti-influenza strategy that warrants further investigation. I nfluenza virus is a single-stranded, negative-sense RNA virus with a genome consisting of 8 segments (1). Like other RNA viruses, influenza virus replicates with extremely low fidelity. Its RNA-dependent RNA polymerase (RdRp) complex, which includes the viral proteins PB1, PB2, PA, and NP (2, 3), has a mutation rate of approximately 2.3 ϫ 10 Ϫ5 substitutions per nucleotide per cell ...

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A novel immunomodulatory mechanism of ribavirin in suppressing natural killer cell function

Cited by 14 publications

References 59 publications

Could Inosine pranobex and Ribavirin in combination restore immune competence in chronic HCV advanced liver disease?

Could Inosine pranobex and Ribavirin in combination restore immune competence in chronic HCV advanced liver disease?

Glycyrrhizin inhibits highly pathogenic H5N1 influenza A virus-induced pro-inflammatory cytokine and chemokine expression in human macrophages

Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs

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