Abstract
Defective viral genomes (DVGs) are truncated and/or rearranged viral genomes produced during virus replication. Described in many RNA virus families, some of them have interfering activity on their parental virus and/or strong immunostimulatory potential, and are being considered in antiviral approaches. Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes spp. that infected millions of humans in the last 15 years. Here, we describe the DVGs arising during CHIKV infection in vitro in mammalian and mosquito cells, and in vivo in experimentally infected Aedes aegypti mosquitoes. We combined experimental and computational approaches to select DVG candidates most likely to have inhibitory activity and showed that, indeed, they strongly interfere with CHIKV replication both in mammalian and mosquito cells. We further demonstrated that some DVGs present broad-spectrum activity, inhibiting several CHIKV strains and other alphaviruses. Finally, we showed that pre-treating Aedes aegypti with DVGs prevented viral dissemination in vivo.
Highlights
Chikungunya virus (CHIKV) is a positive stranded RNA virus belonging to the alphavirus genus (Togaviridae family) that is responsible for chikungunya fever, a dengue-like syndrome with severe joint pain
We use a new approach based on experimental evolution and computational analysis to characterize all defective viral genomes (DVGs) generated in a virus population and identify those with the highest antiviral potential
First described in influenza virus in 1954 by Von Magnus[4], DVGs have since been described in all viral families[5, 6], generally when virus is passaged at high multiplicity of infection (MOI) conditions that favor the appearance of defective genomes requiring helper function from full-length virus
Summary
Chikungunya virus (CHIKV) is a positive stranded RNA virus belonging to the alphavirus genus (Togaviridae family) that is responsible for chikungunya fever, a dengue-like syndrome with severe joint pain This arthropod-borne virus (arbovirus) transmitted by Aedes spp. mosquitoes re-emerged in the last 15 years, posing a serious public health threat by causing two major worldwide epidemics with close to 8 million cases[1,2,3] and other frequent localized outbreaks. DVGs were identified in sera from patients suffering from acute dengue virus infection, but their pathophysiological role remains unknown[12] In humans, their presence correlates with milder disease and better outcome in influenza virus[13] and respiratory syncytial virus infections[10]. All these reasons explain the recent renewed interest in using DVGs as antiviral therapy[14, 15]
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