Abstract
Human cytomegalovirus (HCMV) is a ubiquitous opportunistic pathogen and can be life-threatening for immunocompromised individuals. There is currently no available vaccine for the prevention of HCMV- associated diseases and most of the available antiviral drugs that target viral DNA synthesis become ineffective in treating HCMV mutants that arise after long-term use in immunocompromised patients. Here, we examined the effects of Eltanexor, a second-generation selective inhibitor of nuclear export (SINE), on HCMV replication. Eltanexor effectively inhibits HCMV replication in human foreskin fibroblasts in a dose-dependent manner. Eltanexor does not significantly inhibit viral entry and nuclear import of viral genomic DNA, but rather suppress the transcript and protein levels of viral immediate-early (IE), early (E) and late (L) genes, and abolishes the production of infectious virions. We further found Eltanexor treatment promotes proteasome-mediated degradation of XPO1, which contributes to the nuclear retention of interferon regulatory factor 3 (IRF-3), resulting in increased expression of type I interferon as well as interferon stimulating genes ISG15 and ISG54. This study reveals a novel antiviral mechanism of Eltanexor which suggests it has potential to inhibit a broad spectrum of viral pathogens.
Highlights
Human cytomegalovirus (HCMV) is a β-herpesvirus, which infects up to 60–90% of the world’s population
We examined the effects of Eltanexor (KPT-8602), a newly developed selective inhibitors of nuclear export which showed improved efficacy and in vivo tolerability in clinical trials of hematological malignancies (Hing et al, 2016), on HCMV replication
We aim to examine its effects on HCMV replication
Summary
Human cytomegalovirus (HCMV) is a β-herpesvirus, which infects up to 60–90% of the world’s population. HCMV infection is generally asymptomatic but can cause life-threatening complications in immunocompromised individuals, such as transplant recipients and patients with AIDS. It is a leading cause of congenital infections (Cannon, 2019). Antiviral therapy is hindered by the emergence of mutations in viral DNA polymerase UL54 and viral kinase UL97 which confer resistance to common antiHCMV drugs such as ganciclovir and maribavir (Razonable, 2018). The newly FDA-approved anti-HCMV drug, letermovir, which targets the viral DNA terminase-complex, has been in use for a little over a year; resistant viral variants have already emerged (Douglas et al, 2020). There remains an urgent need to develop new antiviral therapies for HCMV
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