Introduction 2.1. Human iron homeostasis 2.2. Iron and the immune system 2.3. Damaging effects of cellular iron 3. Iron in viral infections 3.1. Role of iron in HBV infection 3.2. Role of iron in HCV infection 3.3 Role of iron in HCMV infection 3.4. Role of iron in HIV infection 4. Conclusion 5. References
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV disease.
m.michaelis@kent.ac.uk (MM) 18 19 Acknowledgements 20 The work was supported by the Hilfe für krebskranke Kinder Frankfurt e.V. and the 21 Frankfurter Stiftung für krebskranke Kinder. 22 23 2 Abstract 24 The thrombopoietin receptor agonist eltrombopag was successfully used 25 against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to 26 immunomodulatory and antiviral drugs. These effects were ascribed to effects of 27 eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also 28 exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV 29 replication in human fibroblasts and adult mesenchymal stem cells infected with six 30 different virus strains and drug-resistant clinical isolates. Eltrombopag also 31 synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. 32 Time-of-addition experiments suggested that eltrombopag interferes with HCMV 33 replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-34 negative cells, and addition of Fe 3+ prevented the anti-HCMV effects, indicating that it 35 inhibits HCMV replication via iron chelation. This may be of particular interest for the 36 treatment of cytopenias after haematopoietic stem cell transplantation, as HCMV 37 reactivation is a major reason for transplantation failure. Since therapeutic 38 eltrombopag concentrations are effective against drug-resistant viruses and 39 synergistically increase the effects of ganciclovir, eltrombopag is also a drug 40 repurposing candidate for the treatment of therapy-refractory HCMV disease. 41 42 Key words: human cytomegalovirus, antiviral therapy, eltrombopag, thrombopietin 43 receptor agonist, drug resistance, iron chelation 44 45 46
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