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The general objective of the projects developed in our team " Virus and Intracellular Trafficking" are to understand how HIV-1, the etiological agent of AIDS, utilizes or perturbs basic cellular pathways (clathrin-dependent endocytosis, nucleo-cytoplasmic trafficking, and DNA repair) to optimize essential steps of the virus life cycle in the natural target cells, T lymphocytes and macrophages, of HIV-1. In turn, characterization of the functions of some HIV-1 regulatory proteins, such as auxiliary regulatory proteins (Nef, Vpr, Vif and Vpu), helped to a better understanding of the cellular processes they are perturbing and using during virus replication in the natural target cells of HIV-1.
Macrophages are cellular targets of HIV-1 and play important roles in virus dissemination and in the establishment of long-lived persistent virus reservoirs in different host tissues. While HIV-1 replication was extensively analyzed in CD4+ T lymphocytes, especially during infection by cell-free virus particles and by virus cell-to-cell transfer between CD4+ T cells, the mechanisms regarding how macrophages could be infected through virus cell-to-cell transfer have been poorly investigated.
The projects developed in the team are thus focused on two main objectives:
1) The first objective is to investigate the molecular and cellular mechanisms required for efficient infection of macrophages by HIV-1 through cell-to-cell transfer, and how the viral regulatory proteins (Nef, Vpr, Vif and Vpu), contribute to this process.
2) The second objective is related to the validation of the approach we have developed for targeting and inhibiting Nef and the gp120 viral envelope glycoprotein with specific camelid single-domain antibody fragments. The projects of this second goal are performed in the context of a joint International Associated Laboratory (LIA) between IPS-CAS (Institut Pasteur Shanghai-Chinese Academy of Sciences, Shanghai) and French Academic Research Institutions (CNRS, Institut Pasteur Paris, University Paris-Descartes and Inserm).
- Dumas, A., Lê-Bury, G., Marie-Anaïs, F., Herit, F., Mazzolini, J., Guilbert, T., Bourdoncle, P., Russell, D.G., Benichou, S., Zahraoui, A., and Niedergang F. 2015. The HIV-1 protein Vpr impairs phagosome maturation by controlling microtubule-dependent trafficking. J. Cell Biol., 211, 359-372.
- Lülf, S., Matz, J., Rouyez, M.C., Järviluoma, A., Saksela, K., Benichou, S. and M. Geyer. (2014) Structural basis for the inhibition of HIV-1 Nef by a high-affinity binding single-domain antibody. Retrovirology, 11, e24.
- Matz, J., Kessler, P., Bouchet, J., Combes, O., Baty, D., Barin, F., Martin, L., Chames*, P. and S. Benichou*. (2013) Straightforward selection of broadly neutralizing single-domain antibodies targeting the conserved CD4 and co-receptor binding sites of HIV-1 gp120. J. Virol., 87, 1137-1149. (*equal contribution)
- Bouchet, J., Hérate, C., Guenzel, C. Vérollet, C. Järviluoma, A., Mazzolini, J., Rafie, S., Chames, P., Saksela, K., Niedergang, F., Maridonneau-Parini, I. and S. Benichou. (2012) Single-domain antibody-SH3 fusions for efficient neutralization of HIV-1 Nef functions. J. Virol., 86, 4856-4867.
- Guenzel, C. A., Hérate, C., Le Rouzic, E., Maidou-Peindara, P., Sadler, H.A., Rouyez, M.-C., Mansky, L.M. and S. Benichou. (2012) Recruitment of the nuclear form of uracil DNA glycosylase into virus particles participates in the full infectivity of HIV-1. J. Virol., 86, 2533-2544.
- Bouchet, J., Basmaciogullari, S., Stolp, B., Fackler, O., Chames, P., Baty, D.* and S. Benichou, * (2011) Llama single-domain antibody fragment for inhibition of the Nef regulatory protein of HIV-1. Blood, 117: 3559-3568. (*equal contribution)
- Maorong Xie obtained a PhD fellowship from the China Scholarship Council (2015).
- Lucie Bracq obtained a PhD fellowship from Institut Pasteur International Network (2015).
- Serge Benichou was appointed as a Scientific Expert of the Specialized Scientific Committee of ANRS ("Agence National pour la Recherche sur le SIDA et les Hépatites VIrales"), Structural Biology and Molecular Genetic (2015-2018).
- The team obtained funding from the HIVERA European Program (2014-2017)
- Serge Benichou was appointed as the Scientific Director of the Sino-French Research Center for Life Sciences from the RuiJing Hospital, JiaoTong University, Shanghai (2013-2014).
- Serge Benichou was awarded as a Visiting Professor by the Chinese Academy of Science, Institut Pasteur Shanghai-Chinese Academy of Sciences, Shanghai (2013-2014).