|Virus and Immunity - CNRS URA 3015|
|HEAD||Schwartz Olivier, PhD / firstname.lastname@example.org|
|MEMBERS||Casartelli Nicoletta (post-doc) / Feldmann Jérôme (post-doc) / Guivel-Benhassine Florence (tech) / Mammano Fabrizio (staff) / Moris Arnaud (staff) / Lepelley Alice (PhD St)
Porrot Françoise (tech) / Rudnicka Dominika (PhD St) / Sol Foulon Nathalie (staff) / Sourisseau Marion (PhD St) / Perrin Virginie (tech) / Vendrame Daniela (PhD St) / Ziani Isma (Secr)
Twenty-five years after its appearance, the HIV/AIDS epidemic represents more than ever a public health threat worldwide. About 35 million people are living with HIV/AIDS as of the end of 2007, most of them originating from emerging countries. Our work focuses on cellular and molecular aspects of HIV-1 replication, and on the mechanisms of recognition of HIV-infected cells by the immune system. Three close and complementary axes of research characterize our scientific activities.
The first axis is aimed at understanding the impact of HIV-1 infection on the biology of T cells. We study the impairment of intracellular trafficking and signaling pathways in infected lymphocytes, and the effects of the HIV-1 Nef protein on these processes. We have demonstrated that Nef manipulates endocytic and signaling pathways in primary T cells. Nef down-regulates the surface expression of CD4 and MHC-I. Nef also affects endocytosis and recycling of the TCR, and the localization of signaling kinases such as Lck. This results in an impaired formation of immunological synapses, when infected T cells encounter APCs. We now wish to understand more precisely what would be the advantages for the virus in manipulating the correct functioning of this synapse
The second axis concerns the cellular and molecular mechanisms regulating HIV-1 replication. We are studying cell-to-cell viral spread. Direct cell-to-cell transfer represents a potent and rapid mode of viral propagation, which likely involves the formation of virological synapses between infected donor cells and uninfected recipients. We have recently underscored the role of ZAP-70, a kinase involved in T-cell activation and immunological synapse formation, in HIV replication. ZAP-70 facilitates cell-to-cell viral transfer and virological synapse formation. This indicates that HIV usurps components of the immunological synapse machinery to ensure its own spread through cell-to-cell contacts. We intend to document the links that may exist between cell activation and HIV spread.
The aim of the third axis is a better knowledge of the interplay between viruses and the immune system of the host. We have focused our studies on APOBEC proteins, and deciphered a primary function of this family of cytidine deaminases, which is to inhibit retrotransposition of endogenous retroviruses. On the other hand, we have performed a long-standing analysis of the mechanisms of antigen presentation by dendritic cells (DCs) and of recognition of HIV-infected cells by antigen-specific CD4+ and CD8+ cytotoxic T lymphocytes (CTLs). We intend to further describe the mechanisms of HIV antigen presentation by DCs, and to unravel the links between antigen presentation and viral transfer.
Keywords: HIV, virus, antigen presentation, dendritic cell, immunological synapse, virological
Esnault C, Heidmann O, Delebecque F, Dewannieux M, Ribet D, Hance AJ, Heidmann T, Schwartz O. APOBEC3G cytidine deaminase inhibits retrotransposition of endogenous retroviruses. Nature. 2005;433:430-433
Moris, A., Pajot, A., Blanchet, F., Guivel-Benhassine, F., Salcedo, M., and Schwartz, O. (2006). Dendritic cells and HIV-specific CD4+ T cells: HIV antigen presentation, T cell activation, viral transfer. Blood. 108(5):1643-51.
Thoulouze, M. I., Sol-Foulon, N., Blanchet, F., Dautry-Varsat, A., Schwartz, O., and Alcover, A. (2006). Human Immunodeficiency Virus Type-1 Infection Impairs the Formation of the Immunological Synapse. Immunity, 547-561.
Fackler, O., Alcover, A. and Schwartz, O. (2007) Modulation of the immunological synapse : a key to HIV-1 pathogenesis ? Nat. Rev. Immunol., 7, 310-7.
Sol-Foulon, N., Sourisseau, M., Porrot, F., Thoulouze, M.I., Trouillet, C., Nobile, C., Blanchet, F., di Bartolo, V., Noraz, N., Taylor, N., Alcover, A., Hivroz, C. and Schwartz, O. (2007) ZAP-70 kinase regulates HIV cell-to-cell spread and virological synapse formation. EMBO J, 26, 516-526.
Activity Reports 2007 - Institut Pasteur
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