Cell biology of viral infections

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Research themes

The identification of cellular functions that are used by viruses to replicate constitutes one of the core expertise of this group. This expertise is largely exploited for the identification of therapeutic targets and anti-viral molecules and for the study of mechanisms and consequences of energetic perturbation occurring during the infectious process.

Analysis of “omics” data and drug discovery

Viral infections cause major public health and socio-economical problems. The therapeutic arsenal is very limited, poorly efficient, essentially directed towards virus components and favors the emergence of resistant strains. The current status pleads in favor of a new therapeutic strategy targeting the cellular functions that are manipulated by viruses to replicate.V-H interactomic
Viruses are excellent manipulators of cellular functions. Advanced technologies now allow the construction of comprehensive maps of interactions between virus and host proteins. These maps have been constructed for several viruses (HIV, HCV, Dengue, Influenza) and revealed to be instrumental for the identification pro- and anti-viral cellular functions. Although still in its infancy, the construction and analysis of interaction network is already paving the way of network pharmacology and rational drug repositioning.
In the Lyonbiopôle center of Infectiology, we have created a platform of systems biology for the rational identification of new therapeutic targets and molecules. With its unique database integrating interactomics and functional genomics and its knowledge on how viruses perturb cell host functions, the platform can identify relevant targets for the development of host-oriented molecules. Network pharmacology allows selection of therapeutic molecules, using a drug repurposing strategy and an original library of interfering peptides targeting cellular generic processes. The platform now offers tools to manipulate a large panel of original therapeutic targets for infectious and non-communicable chronic diseases. Internal lead programs first concerned influenza A, hepatitis B and hepatitis C viruses. Second wave programs are concerning HIV and viruses of medical interest as well as Insulin resistance and mitochondrion dysfunction. In addition, the platform has developed an innovative method for reading transcriptomic data from pathway reconstruction to drug discovery. Seven patents have been filled since the beginning of this program.

Cross-talks between viral infections and metabolism

The relationship between viral infection and host metabolism is particularly studied through the models of viral hepatitis B and C. Both viruses exemplify how viruses can benefit from their interaction with the bio-energetic metabolism of the cell. The hepatitis C virus directly impacts the bio-energetic and central carbon metabolism of hepatocytes with obvious biological and clinical implications at the host level. Indeed, chronic hepatitis C infection leads to a particular metabolic syndrome associating insulin resistance, fatty liver and hypobetalipoproteinemia. HCV replication is closely dependent on lipid metabolism, including synthesis of VLDL, at all stages of the replication cycle, Our team has shown that highly infectious HCV particles circulating in patients are hybrid lipo-viral particles (LVP), which are betalipoproteins modified by the presence of a nucleocapsid in the lipid core and of viral envelope proteins at the surface of these particles. The team is now focusing on the identification of signals delivered by these particles to the adjacent liver tissue or to peripheral tissues to understand the insulin resistance that characterizes this infection.

LVP

Although the hepatitis B virus induces only low metabolic disturbances in the liver of the host, it was characterized as a “metabolovirus” because its replication is closely dependent on metabolic signals integrated by hepatocytes through nuclear receptors and epigenetic regulation of viral gene transcription. The team has shown in particular that the bile salt nuclear receptor FXR is a crucial factor in the control of viral replication and continues to study the role of fasting and satiety signals, as well as the energy status of the cell during HBV replication.

 

 

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