|Virus and Immunity - CNRS URA 3015|
|HEAD||Prof. Olivier SCHWARTZ / firstname.lastname@example.org|
|MEMBERS||Casartelli Nicoletta / Feldmann Jérôme / Guivel-Benhassine Florence / Lepelley Alice / Louis Stéphanie / Malbec Marine / Mammano Fabrizio / Monel Blandine / Nobile Cinzia / Porrot Françoise / Roesch Ferdinand / Vendrame Daniela / Ziani Isma
Twenty-fiveyears after its appearance, the HIV/AIDS epidemic represents more than ever a public health threat worldwide. More than 30 million people are living with HIV/AIDS as of the end of 2008, 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, and modifies the dynamics of the cytoskeleton. We are currently characterizing the effects of HIV infection on the biology of the cell, with a particular interest for the shape, the viability, the migration properties of infected cells. Finally, inhibiting Nef activity may represent a new target for the development of novel therapeutic strategies against HIV. Our aim is to design experimental systems allowing the screening of such compounds.
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 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 adaptative and innate immune systems of the host. On one hand, 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 and of recognition of HIV-infected cells by antigen-specific CD4+ and CD8+ cytotoxic T lymphocytes (CTLs). We are also examining how HIV infection triggers production of type-I interferons (IFNs) and other cytokines in various cell types, including plasmacytoid Dendritic cells. We are also currently analyzing the impact of IFNs on virus replication and cell-cell transfer, and on viral antigen presentation.
Keywords: HIV, virus, antigen presentation, dendritic cell, immunological synapse, virological synapse
Rudnicka, D and O. Schwartz. 2009 News & Views: “Intrusive HIV-1 infected cells” Nature Immunology 9:933-4
Vendrame D, Sourisseau M, Perrin V, Schwartz O and Mammano F. 2009 Partial Inhibition of HIV Replication by Type-I Interferons: impact of Cell-to-Cell Viral Transfer. J Virol 83(20):10527-37
Rudnicka, D., J. Feldmann, F. Porrot, S. Wietgrefe, S. Guadagnini, M. C. Prevost, J. Estaquier, A. Haase, N. Sol-Foulon, and O. Schwartz. 2009.Simultaneous HIV Cell-to-Cell Transmission To Multiple Targets Through Polysynapses. J Virol 83:6234-46
Casartelli N, Guivel-Benhassine F, Bouziat R, Brandler S, Schwartz O and Moris A. 2010 The antiviral factor APOBEC-3G improves CTL recognition of HIV infected T cells. J Exp Med 207: 39-49
Nobile C, Rudnicka D, Hasan M, Aulner N, Porrot F, Machu C, Renaud O, Prévost MC, Hivroz C, Schwartz O, Sol-Foulon N. 2010 HIV-1 Nef induces filopodia and modulates migration of infected lymphocytes. J Virol In press
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