The arthropod-borne flaviviruses are important human pathogens, and a deeper understanding of the virus–host cell interaction is required to identify cellular targets that can be used as therapeutic candidates. It is well reported that the flaviviruses hijack several cellular functions, such as exosome-mediated cell communication during infection, which is modulated by the delivery of the exosomal cargo of pro- or antiviral molecules to the receiving host cells. Therefore, to study the role of exosomes during flavivirus infections is essential, not only to understand its relevance in virus–host interaction, but also to identify molecular factors that may contribute to the development of new strategies to block these viral infections. This review explores the implications of exosomes in flavivirus dissemination and transmission from the vector to human host cells, as well as their involvement in the host immune response. The hypothesis about exosomes as a transplacental infection route of ZIKV and the paradox effect or the dual role of exosomes released during flavivirus infection are also discussed here. Although several studies have been performed in order to identify and characterize cellular and viral molecules released in exosomes, it is not clear how all of these components participate in viral pathogenesis. Further studies will determine the balance between protective and harmful exosomes secreted by flavivirus infected cells, the characteristics and components that distinguish them both, and how they could be a factor that determines the infection outcome.

Cellular cyclophilins (Cyps) such as cyclophilin A (CypA) have emerged as key players at the virus-host interface. As host factors required for the replication of many unrelated viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV) and coronaviruses (CoVs), Cyps are attractive targets for antiviral therapy. However, a clear understanding of how these viruses exploit Cyps to promote their replication has yet to be elucidated. Recent findings suggest that CypA contributes to cloaking of viral replication intermediates, an evasion strategy that prevents detection of viral nucleic acid by innate immune sensors. Furthermore, Cyps are emerging to have roles in regulation of cellular antiviral signaling pathways. Recruitment of Cyps by viral proteins may interfere with their ability to regulate these signaling factors. Consistent with disruption of viral cloaking and innate immune evasion, treatment with Cyp inhibitors such as cyclosporine A (CsA) restores antiviral innate immunity and induces expression of a subset of antiviral genes that restrict viral infection, which may help to explain the broad antiviral spectrum of CsA. In this review, we provide an overview of the roles of CypA in viral cloaking and evasion of innate immunity, focusing on the underlying mechanisms and new perspectives for antiviral therapies.

Cyclophilins are cellular peptidyl-prolyl isomerases that play an important role in viral infections, with demonstrated roles in the replication of hepatitis C virus (HCV) and other viruses in the Flaviviridae family, such as dengue virus (DENV) and yellow fever virus (YFV). Here, we discuss the roles of cyclophilins in HCV infection and provide a comprehensive overview of the mechanisms underlying the requirement for cyclophilins during HCV replication. Notably, cyclophilin inhibitor therapy has been demonstrated to be effective in reducing HCV replication in chronically infected patients. While the roles of cyclophilins are relatively well-understood for HCV infection, cyclophilins are more recently emerging as host factors for flavivirus infection as well, providing potential new therapeutic avenues for these viral infections which currently lack antiviral therapies. However, further studies are required to elucidate the roles of cyclophilins in flavivirus replication. Here, we review the current knowledge of the role of cyclophilins in HCV infection to provide a conceptual framework to understand how cyclophilins may contribute to other viral infections, such as DENV and YFV. Improved understanding of the roles of cyclophilins in viral infection may open perspectives for the development of cyclophilin inhibitors as effective antiviral therapeutics for HCV and related viruses.

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