Institut de Biologie StructuraleGrenoble / France

Contact person(s) related to this article / WEISSENHORN Winfried


Group leader: Winfried Weissenhorn

ATIP-Avenir team : Jan Kadlec


• Winfried Weissenhorn, Professor , University Grenoble Alpes
• Pauline Macheboeuf, Researcher CR2 CNRS
• Nolwenn Miguet, Technician and PhD student, University Grenoble Alpes
• Delphine Guilligay, Research Engineer CNRS

• Christophe Caillat, Postdoctoral fellow
• Guidenn Sulbaran Machado, Postdoctorant
• Pavel Mikulecky, Postdoctoral fellow
• Juan-Luis Loredo-Varela, Postdoctoral fellow
• Geraldine Mayeux, PhD Student

Research topics

The focus of our research is to obtain insight into the structural and functional role of proteins and complexes that control and catalyze entry and budding processes of enveloped viruses such as HIV-1. We employ a combination of molecular biology, protein chemistry, X-ray crystallography and electron microscopy (collaboration) to address these questions.

Enveloped virus budding
Enveloped viruses express structural proteins that together with a distinct set of cellular proteins mediate virus assembly at cellular membranes and the release of infectious virions. We study cellular complexes such as ESCRT proteins and their regulators to understand the molecular mechanism of virus release by membrane fission.

Model for ESCRT-III driven HIV-1 budding
ESCRT-III is recruited once Gag assembly has been completed and Tsg101 and Alix are present at the budding site. First, CHMP4B is recruited and polymerizes within the membrane neck structure (green polymer), which may induce a first constriction of the neck. CHMP4B filaments then form the platform to recruit CHMP2B (red) alone or CHMP3-CHMP2A filaments (red) that can form dome-like structures. These polymers have a high affinity for membrane, which can induce membrane neck constriction and together with the action of VPS4 fission. VPS4-driven disassembly of ESCRT-III filaments and fission are likely concomitant processes.

HIV-1 entry
The HIV-1 envelope glycoprotein is composed of a receptor binding subunit, gp120 that is non-covalently linked to the membrane anchored fusion protein, gp41. Triggered by cellular receptor binding, the trimeric envelope complex mediates fusion of viral and cellular membranes through the rearrangement of the fusion protein subunit into a six helical bundle core structure. Our interest is to understand the structural transitions that gp41 undergoes from a native conformation to a fusion intermediate conformation and the final post fusion structure. Because gp41 contains highly conserved epitopes within its membrane proximal region (MPR), we aim to understand their conformation that is recognized by broadly neutralizing antibodies in order to exploit the structural knowledge for vaccine development.

Innate immune factors
The early step of infection triggers the expression of interferon-induced genes that act during an early defense mechanism. We study the structure and regulation of tetherin that physically links enveloped viruses including HIV-1 to the plasma membrane and targets them for lysosomal degradation in the absence of the viral antagonist. Likewise other restriction factors target budding and entry processes of a number of enveloped viruses and we study their structure to gain insight into their function.


HIV-1, ESCRT, membrane fission, budding, X-ray crystallography.

Selected recent publications

• Gray, E.R., Brookes, J.C., Caillat, C., Turbé, V., Webb, B.L.J., Granger, L.A., Miller, B.S., McCoy, L.E., El Khattabi, M., Verrips, C.T., Weiss, R.A., Duffy, D.M., Weissenhorn, W. and McKendry, R.A. (2017) Unravelling the Molecular Basis of High Affinity Nanobodies against HIV p24: In Vitro Functional, Structural, and in Silico Insights. ACS Infect Dis 14;3(7):479-491.
• Saletti, D, Radzimanowski, J., Effantin, G., Midtvedt, D., Mangenot, S, Weissenhorn, W, Bassereau, P. and Bally, M. (2017) The Matrix protein M1 from influenza C virus induces tubular membrane invaginations in an in vitro cell membrane model. Sci Rep 7:40801
• Effantin, G., Estrozi, L., Ashman, N., Renesto, P., Stanke, N., Lindemann, D., Schoehn, G., and Weissenhorn, W. (2016) Cryo-electron microscopy Structure of the native Prototype Foamy Virus Glycoprotein and virus Architecture. PLoS Pathogens 12(7):e1005721
• C. Caillat, P. Macheboeuf, Y. Wu, A.A. McCarthy, E. Boeri-Erba, G. Effantin, H.G. Gottlinger, W. Weissenhorn and P. Renesto (2015) Asymmetric ring structure of Vps4 required for ESCRT-III disassembly. Nat Commun 6:8781.
• M.G. Bego, É. A. Côt, N. Aschman, J. Mercier, W. Weissenhorn and E. A. Cohen (2015) Human Immunodeficiency Virus Accessory Protein Vpu Inhibits the Antiviral Response of Plasmacytoid Dendritic Cells for Innate Immune Evasion. PLoS Pathogen, 11(7):e1005024.
• D. Lutje Hulsik, Y. Y. Liu, N. M. Strokappe, S. Battella, M. El Khattabi, L.E. McCoy, C. Sabin, A. Hinz, M. Hock, P. Macheboeuf, A.M.J.J. Bonvin, J.P.M. Langedijk, D. Davis, A. Forsman-Quigley, M. M.I. Aasa-Chapman, M. S. Seaman, A. Ramos, P. Poignard, A. Favier, J.-P. Simorre, R. A. Weiss, C. T. Verrips, W. Weissenhorn and L. Rutten (2013) A gp41 MPER-specific llama VHH requires a hydrophobic CDR3 for neutralization but not for antigen recognition. PLoS Pathogens, 9 (3) e1003202
• V. Buzon, G. Natrajan, D. Schibli, F. Campelo, M. M. Kozlov, and W. Weissenhorn (2010) Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions. PLoS Pathogens, 6(5) e1000880
• A. Hinz, N.Miguet, G. Natrajan, Y. Usami, H. Yamanaka, P. Renesto, B. Hartlieb, A. A. McCarthy, J.-P. Simorre, H. Gottlinger and W. Weissenhorn (2010) Structural basis of HIV-1 tethering to membranes by the Bst2/tetherin ectodomain. Cell Host Microbe, 7, 314-323.
• G. Fabrikant, S. Lata, J. D. Riches, J.A. Briggs, W. Weissenhorn and M.M. Kozlov (2009) Computational model of membrane fission catalyzed by ESCRT-III. PLoS Comput Biol 5(11), e1000575.
• Lata S, Schoehn G, Jain A, Pires R, Piehler J, Gottlinger HG, Weissenhorn W. (2008) Helical structures of ESCRT-III are disassembled by VPS4. Science 321, 1354-1357.
• T. Muziol, E. Pineda-Molina, G. Schoehn, R. Ravelli, A. Zamborlini, Y. Usami, H. Göttlinger, and W. Weissenhorn (2006) Structural basis for budding by the ESCRT-III factor CHMP3. Dev. Cell, 10, 821-830.

The complete publication list is available here.

The complete list of PhD thesis can be found here