Molecular determinants of attenuation of chikungunya virus in mosquitoes and potential role of the mosquito in the emergence of drug resistance.

Arboviruses can cause severe diseases such as hemorrhagic fever, encephalitis and arthritis. Some arboviruses, including the chikungunya virus (CHIKV), are significant global health threats because of their high disease burden, their widespread (re-)emergence and the lack of vaccines or therapeutics. Furthermore, there is a lack of knowledge on the potential emergence of antiviral drug-resistant arboviruses once such drugs may become available. We previously observed that a CHIKV variant resistant to the antiviral drug T-705 replicates remarkably less efficient in mosquitoes than the wild type virus. In this project, we will study the mechanism of the abrogated replication fitness of this virus in mosquitoes. We will also determine whether this mechanism is conserved among other mosquito-borne viruses. This part of the project will thus provide key information on determinants of the mosquito tropism of CHIKV. Next we will carry out an in depth study on the potential role of the mosquito vector in the development of drug-resistant CHIKV. Once anti-CHIKV drugs will become available, mosquitoes will ingest the drug during blood feeding on patients that are being treated with such drug. There exists no knowledge on the effect that such drugs may elicit on virus(es) that the mosquito may carry. We will study (i) the effect of experimental CHIKV inhibitors on CHIKV replication in the mosquito and (ii) whether drug-resistant variants may or may not develop in mosquitoes.