Nuclear trafficking in viral infection and immunity

Viruses that replicate in the nucleus (e.g. HIV and influenza A virus) rely on the nuclear pore complex (NPC) and the nuclear architecture for the replication of their genome, which can persist in the nucleus as an integrated cassette within the host cell chromatin, as episomes or as complex genomic entities.

NPCs can favour viral replication by offering a micro-environment rich in nucleotides, a hotspot for components of the SUMO machinery (e.g. RanBP2, RanGAP1, Ubc9, SENP2) and a highly-connected network with the cytoskeleton and the nuclear architecture. However, NPCs are also key modulators of innate immunity since they regulate the import of innate immune transcription factors (e.g. IRF proteins or NF-κB) and antiviral factors (e.g. TRIM5α), and the export of transcripts that code for cytokines (e.g. IL-6 mRNA). Similarly, nuclear domains such as PML nuclear bodies (PML-NBs) can control viral genome expression and the establishment of latency, but are also a hotspot of antiviral defense.

It is the central nature of NPCs and other nuclear structures in both viral replication and innate immunity that drives our research projects.

Project 1: HIV trafficking and nuclear translocation. Over the years, our team has studied in-depth the mechanisms underlying HIV nuclear import and uncoating. We recently identified an atypical nuclear localisation signal in HIV-1 capsid that is recognised by Transportin-1 to carry HIV-1 capsids through NPCs. We are currently developing inhibitors of the Transportin-1/capsid binding interface that act as antivirals that specifically target nuclear import with high potency and low toxicity.
Project 2: Control of the innate immune response to influenza A virus by RanBP2. RanBP2 is a component of the cytoplasmic fibrils of NPCs. We previously examined its importance in mediating HIV-1 docking to NPCs, and in modulating the function of TRIM5α in dendritic cells. Our current research examines how RanBP2 modulates the production of pro-inflammatory cytokines following influenza A virus infection, and how this is disrupted in the rare genetic disorder Acute Necrotizing Encephalopathy (ANE1).

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The VTRIS team:


The team in April 2024
At the back, from left to right: S. Nisole, G. Beucher, I. Bribes, R. Gaye, S. Desgraupes, M. Gonzalez, M. Seite, A. Decorsière. At the front, from left to right: J. Zoladek, 
S. Perrin, M. Cannac, N. Arhel


The team in April 2023

From left to right: S. Nisole, T. Léocadie, A. Decorsière, S. Perrin, E. Quevarec, C. Fournie, S. Desgraupes, N. Arhel,
I. Bribès, B. Gouy, J. Zoladek.


The team in March 2022
From left to right: N. Arhel, E. Arsac,S. Nisole, P. Gonin, A. Decorsière, M. Cartron, A. Vidal, A. Boulay, J. Zoladek, C. Chamontin.


The team in March 2021
From left to right: C. Chamontin, N. Arhel, S. Nisole, M.F. Martin, H. Abiven, G. Maarifi, J. Fernandez, P. Nouaux, E. Gerber-Tichet, A. Boulay, Q. Hertel, F. Blanchet.

Team leader

Nathalie J Arhel

Research Director at CNRS
Invited Professor at McGill University

IN BRIEF

The VTRIS team was created on January 1st 2017, following an international call for senior group leaders from the IRIM institute. It is supported by the regional excellence consortium (Labex) EpiGenMed.

Funding

           

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