Description du projet
Imagerie de la pénétration cellulaire du VIH pour aider à concevoir un vaccin
La récente découverte d’anticorps neutralisants le VIH-1 a relancé les efforts vaccinaux. Pour aider à la conception d’un vaccin rationnel, les scientifiques du projet FUSION, financé par l’UE, ont pour objectif de comprendre le mécanisme sous-jacent à la reconnaissance d’une cible et de caractériser les réponses anticorps polyclonales. Pour cela, ils utiliseront les techniques de pointe d’imagerie à résolution temporelle pour visualiser la fusion du VIH-1 à la surface de cellules vivantes et décoder le mécanisme par lequel différents anticorps neutralisants perturbent cette fusion qui est conservée pour différentes lignées de VIH. En dévoilant des interactions clés virus-cellule hôte au niveau moléculaire, FUSION tracera la voie à la conception de nouveaux médicaments et vaccins.
Objectif
The HIV-1 vaccine research has re-emerged in the last few years due to the identification of antibodies that neutralize most HIV-1 circulating strains. A deeper understanding of the mechanistic mode of target recognition for these antibodies represents a big hope in the field. This project aims at understanding and characterizing polyclonal antibody responses to aid rational vaccine design via radically new technologies on light microscopy. The molecular mechanism of time-resolved HIV-1 fusion will be visualized and quantified on the surface of living cells by combining real-time single virus tracking, fluorescence fluctuation spectroscopy and 3D single molecule localization microscopy (SMLM) imaging. The implementation of a new technology that allows three-dimensional nanometre localization of single particles will allow us to multiplex single molecule experiments with functional readouts for single-virus HIV-1 fusion simultaneously. Here, I will systematically establish the mechanism of action of different families of neutralizing antibodies and how they disrupt the three-step HIV fusion reaction, conserved among different HIV tropism, recently discovered by our group. I will unveil the molecular insights on the precise Env-induced, time-resolved stoichiometry of CD4 and co-receptors (CCR5 or CXCR4) in the presence and absence of different combinations of bNAbs and study their impact on HIV transmission. FUSION will open new avenues to design putative drugs that target host-specific receptor and co-receptor oligomeric states to block HIV-1 fusion. This project systematically applies cutting-edge time-resolved imaging approaches as a gold standard to ascertain how different combinations of bNAbs perturb the HIV fusion mechanism in CD4+ T cells and macrophages. I will establish a world-class laboratory in HIV-1 and single molecule microscopy. I will decipher several key virus–host cell interactions at molecular level and contribute to rational vaccine and drug desig
Champ scientifique
- natural sciencesbiological sciencesmicrobiologyvirology
- natural sciencesphysical sciencesopticsmicroscopy
- medical and health scienceshealth sciencesinfectious diseasesRNA virusesHIV
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccines
- natural sciencesphysical sciencesopticsspectroscopy
Mots‑clés
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
WC2R 2LS London
Royaume-Uni