Viruses use, misuse and abuse their hosts to replicate, escape immune responses and invade new cells or organisms. By studying and comparing virus genus and species, we aim to better understand how some human viral pathogens, in particular hepatitis C virus (HCV) and Dengue virus, can establish persistent versus acute infections, respectively, and how this is determined by interactions with host pathways.
Virus interconnection with lipid metabolism may find its most remarkable feature with the formation of hybrid infectious HCV particles that combine viral and lipoprotein components, which strongly impacts virus escape from neutralizing antibodies and entry into cells. HCV particles assemble along the VLDL biosynthetic pathway and are released from hepatocytes as entities varying in their degree of association with different lipid and apolipoprotein types. Furthermore, the most early stages of HCV assembly have been associated to key enzymes and cellular structures involved in storage of triglycerides and cholesterol, i.e. the lipid droplets, which are also precursors of VLDLs. Consistently, HCV enters cells by using different entry co-factors that are lipoprotein and cholesterol transfer receptors. Using ex vivo and in vivo models, i.e. human liver mice, our studies aim to unravel pivotal determinants of the intersections between HCV replication and lipid metabolism.
Upon sensing invading viruses, host cells trigger interferons (IFNs) production that suppress viral spread. Many viruses, including HCV and dengue virus (DENV) have thus evolved mechanisms that preclude this response within infected cells. Nonetheless, these viral infections strongly induce IFN expression in infected humans, suggesting the existence of alternative pathogen-sensing mechanisms. Consistently, we recently demonstrated that exosomes, i.e. small extracellular vesicles, produced by infected cells, transfer immunostimulatory viral RNAs to immune cells, plasmacytoid dendritic cells (pDCs), which, in response, robustly produce IFN. We are defining the series of host-virus interactions that permit the biogenesis of this previously unrecognized immunostimulatory RNA carrier. By deciphering shared and specific host-virus interplays using evolutionary divergent viruses, i.e. HCV and DENV, we will provide a framework of antiviral responses that may have evolved to protect the host against other viruses that also blunt pathogen-sensing within infected cells.
Furthermore, we focus on the interplay between viruses and the autophagy machinery. Autophagy is a major intracellular pathway for the degradation via vesicles formation that engulfs intracellular cytoplasmic organelles and proteins aggregates in response to cellular stresses. Consistently, autophagy enables cells to resist intrusion by bacteria, viruses and parasites by destroying them. Autophagy also regulates the secretion of IFN and inflammatory molecules. Nonetheless, we and others demonstrated that HCV and DENV subvert autophagy pathway during virus replication. The functional relationships between autophagy and viruses are under investigation.
Finally, our long-term interest is to develop innovative biotherapies against infectious diseases, by targeting different steps of virus replication, and more particularly, those involving assembly and entry of viral particles. We expect that the deep understanding of the immune mechanisms that restrict infection or, alternatively, that are counteracted, subverted or perverted by pathogens, will facilitate the development of these antiviral strategies. Such applications require the development of viral engineering technologies and of viral vector platforms, aiming to develop novel tools and/or concepts in gene therapy, vaccinology, immunotherapy and design of antiviral agents. We have heavily invested over the last period in building translational projects towards such developments.

Key words: Virology, Immunology, Vaccinology, Gene therapy, Virus engineering, HCV, Dengue, Lentivirus, Lipoprotein, Innate response