Projets de Recherche - Axe 1 (PI: A. Cimarelli)

Axis 1 (PI: Andrea Cimarelli): Identification and characterization of cellular factors that modulate HIV replication and extrapolation to other RNA viruses

The focus of this axis is to decipher the cell-virus interface through the study of the multitude of interactions established between cellular and viral proteins that allow, or in some instances impede, viral replication. Some ongoing projects:

• Antiviral Roles of the Interferon-Induced Transmembrane Family (IFITMs) in membrane fusogenicity

IFITMs are a family of broad antiviral factors targeting viruses as diverse as Ebola virus and HIV at two steps: viral entry, by sequestering incoming virions in endosomes and production of infectious virions from infected cells (negative imprinting of virions). We are currently using unbiased omics approaches to identify cellular partners of IFITMs and physical changes at the basis of the fusogenicity defects of membranes. Our goal is to identify the underlying mechanism of IFITM inhibition which in the long run may pave the way for the development of pan-viral strategies of viral control mimicking these proteins.

The figure presents a cartoon view of the mechanisms of action of IFITMs during the viral life cycle

• Interferon-Sensitive protein 20 (ISG20) as a viral translation sentinel

The interferon- sensitive gene 20 (ISG20) is a member of the DEDD superfamily of RNA/DNA exonucleases that exhibits broad antiviral activities. We have recently shown that ISG20 does not degrade certain viral RNAs, but rather prevents their translation.   At present, we are using different techniques to apprehend the exact mechanism of inhibition by ISG20 as well as its specificities Our long-term goal is to characterize a novel mechanism of viral control that could potentially give insights into novel strategies of viral modulation.

The figure presents cells either infected with a VSV-GFP virus, or  transfected with a GFP-coding plasmid both regarded as non-self genetic elements by ISG20. The structure of ISG20 as determined in Horio et al, FEBS let. 2004 with residues that inactivate or not the protein’s functions in violet and yellow, respectively.

• Microtubules as a novel frontier in the field of host pathogen interactions

Microtubules (MTs) are the highways through which cargos and multiprotein complexes move within the cell. Viruses have a long, documented history of using and sometimes altering the MT network for their own purposes by co-opting a number of cellular co-factors, but wheter the cell could in turn mount antiviral responses via the MT remained unknown. Our recent study indicated that the cell can rewire their MT network for antiviral purposes in response to type I interferons, leading to inhibition of a broad spectrum of viruses that encompasses Retroviridae, as well as negative and positive-strand RNA viruses. We have identified Trim69, member of the large Tripartite motif family as the key factor at the basis of this reorganization and we are now determining of this protein works. Our long-term goal is to decorticate the mechanisms and diversity of actors involved in this novel facet of host-pathogen interactions.

Funding (in alphabetical order):
ANR, ANRS, CNRS, FINOVI, FRM, JoRISS, Région Auvergne Rhône Alpes, Sidaction