The War on Arboviruses: Leveraging Co-Infection Inhibition and Endogenous Viral Elements Towards Inhibiting Arbovirus Horizontal Transmission

SUMMARY Clinically significant arboviruses like dengue virus, zika virus, and chikungunya virus currently impose a major global health crisis due to their high frequency of transmission and from the lack of approved antivirals and vaccines against them. As current countermeasure strategies have proven insufficient in counteracting the horizontal transmission of arboviruses, there is a high demand for novel and effective strategies to reduce the incidence rate of these arboviruses. One such mechanism that could be explored is coinfection inhibition: the impairment to arbovirus fitness from co-infecting arbovirus species. Studies in humans and Aedes aegypti mosquitoes have revealed a trend in impairment to the viral load and infection rate of select arboviruses. While there is potential in exploiting this mechanism to inhibit arbovirus transmission, there are many limitations to using intact viruses to compete with clinically significant arboviruses, namely the requirement for a sustained infection to enable arbovirus protection. One potential solution to this would be the application of arbovirus-derived endogenous viral elements as an intrinsic measure of defense against arbovirus infection in mosquito vectors. These elements, incorporated into the genome of mosquito vectors, could encode for dysfunctional viral proteins designed to block functional viral proteins from their substrates. The efficacy of candidate endogenous viral elements could be experimentally validated in an in vitro C6/36 cell model and subsequently in a live Ae. aegypti transgenic model. Given that some arboviruses like dengue virus have been shown to negatively impact female Ae. aegypti survival and reproduction, it would be expected that transgenic Ae. aegypti would be able to outcompete wild-type strains, thus enabling the fixation of the transgene(s) into the population. Ultimately, arbovirus-derived endogenous viral elements exhibit substantial potential as an intrinsic countermeasure against arbovirus infections in mosquito vectors towards impairing the primary mode of arbovirus transmission and thus, reducing infection rates in humans.