Abstract
The mosquito-borne dengue virus (DENV) is a cause of significant global health burden, with an estimated 390 million infections occurring annually. However, no licensed vaccine or specific antiviral treatment for dengue is available. DENV interacts with host cell factors to complete its life cycle although this virus-host interplay remains to be fully elucidated. Many studies have identified the ubiquitin proteasome pathway (UPP) to be important for successful DENV production, but how the UPP contributes to DENV life cycle as host factors remains ill defined. We show here that proteasome inhibition decouples infectious virus production from viral RNA replication in antibody-dependent infection of THP-1 cells. Molecular and imaging analyses in β-lactone treated THP-1 cells suggest that proteasome function does not prevent virus assembly but rather DENV egress. Intriguingly, the licensed proteasome inhibitor, bortezomib, is able to inhibit DENV titers at low nanomolar drug concentrations for different strains of all four serotypes of DENV in primary monocytes. Furthermore, bortezomib treatment of DENV-infected mice inhibited the spread of DENV in the spleen as well as the overall pathological changes. Our findings suggest that preventing DENV egress through proteasome inhibition could be a suitable therapeutic strategy against dengue.
Highlights
Dengue has emerged to be the most important mosquito-borne viral disease globally
A possible rapid approach to a specific therapeutic for dengue is to use a licensed inhibitor of a host factor critically required by dengue virus (DENV) to complete its life cycle
One such set of factors is in the ubiquitin proteasome pathway (UPP)
Summary
An estimated 390 million infections occur annually while another 3 billion people that live in or travel to the tropics are at constant risk of infection with any of the four dengue virus (DENV) serotypes [1]. An important consideration is whether vaccination can avoid antibody-enhanced infection that is epidemiologically associated with increased risk of severe dengue [4,5]. Effective antiviral therapies against dengue would address disease burden imposed by dengue, it would be useful in vaccinated populations should vaccine failure occur. Antiviral therapies must be effective against both primary and secondary infections; the latter may be enhanced by the presence of heterologous antibodies and is associated with increased risk of severe disease
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