Please visit us for the latest edition of the Wright-Fleming Institute,
Series of seminars on infections and immunity
Professor Olivier Schwartz
The long-standing interest of our laboratory is the study of the molecular and cellular mechanisms that regulate virus replication and interaction with the host. We are studying HIV, Chikungunya virus, Zika virus and, more recently, SARS-CoV-2. We investigate the role of restriction factors, cellular proteins that are often induced by IFN, and thus essential components of the host’s innate immunity, which inhibit virus replication in discrete steps in the viral life cycle. We also study how the humoral immune response controls virus replication.
Contributions to science
1) Activity of non-neutralizing and largely neutralizing (bNAbs) anti-HIV-1 antibodies
We identified a subset of bNAbs that inhibit both cell-free and cell-mediated infection in CD4 + primary lymphocytes. These antibodies accumulate at virological synapses and impair cluster formation and fusion of infected and target cells as well as the transfer of viral material to uninfected T cells. In addition, they block the transmission of viral cells to pDCs, thereby disrupting type I IFN production.
We have also characterized bNAbs that exert antibody-dependent cellular cytotoxicity in culture and kill HIV-1 infected lymphocytes through NK exposure. The landscape of surface Env epitope exposure and the sensitivity of infected cells to ADCC vary significantly between virus strains. Efficient ADCC requires sustained cell surface binding of bNAbs to Env, and the combination of bNAbs enables strong killing activity. In addition, reactivated infected cells from HIV-positive individuals expose heterogeneous Env epitope patterns, the levels of which are often, but not always sufficient, to trigger killing by bNAbs. Our study outlined the parameters that control the ADCC activity of bNAbs and supports the use of the most effective antibodies to cleanse the virus reservoir.
Dufloo J., Bruel T., Schwartz O. HIV-1 transmission from cell to cell and largely neutralizing antibodies. Retrovirology. 2018, July 28; 15 (1): 51.
Bruel T., Guivel-Benhassine F., Amraoui S., Malbec M., Richard L., Bourdic K., Donahue DA, Lorin V., Casartelli N., Noël N., Lambotte O., Mouquet H., Schwartz O. Elimination of HIV-1 infected cells by largely neutralizing antibodies. Nature Communications, March 3, 2016; 7: 10844. doi: 10.1038 / ncomms10844.
Malbec M., Porrot F., Rua R., Horwitz J., Klein F., Halper-Stromberg A., Scheid J., Eden C., Mouquet H., Nussenzweig MC, Schwartz O. 2013. Broadly neutralizing antibodies, which inhibit cell-to-cell transmission of HIV-1. J. Exp. Med. December 16; 210 (13): 2813-21.
2) HIV, dendritic cells and macrophages, role of SAMHD1
We examined the interactions between HIV-1 / HIV-2 and dendritic cells and macrophages. We reported that HIV-2 Vpx enables unproductive infection of dormant CD4 + T cells by degrading SAMHD1, but does not confer the ability of HIV-2 to efficiently infect macrophages. In these cells, an entry defect prevents virus fusion and reverse transcription independently of SAMHD1. We suggested that HIV-2, like HIV-1, does not productively infect MDDCs, possibly to avoid triggering an immune response mediated by these cells. We have also shown that MDDCs are poorly sensitive to HIV-1 and HIV-2 infections due to low CD4 cell surface levels.
We examined the consequences of the antiviral activity of SAMHD1 on the presentation of HIV-1 antigens and innate cognition in MDDCs. We have shown that SAMHD1 restricts the transmission of HIV-1 from cell to cell and limits immune detection in these cells.
Chauveau L., Donahue DA, Monel B., Porrot F., Bruel T., Richard L., Casartelli N., Schwartz O. HIV fusion in dendritic cells occurs mainly on the surface and is limited by low CD4 levels. J Virol. 2017 Aug 16. pii: JVI.01248-17.
Chauveau L, Puigdomenech I, Ayinde D, Roesch F, Porrot F, Bruni D, Visseaux B, Descamps D, Schwartz O. 2015. HIV-2 infects dormant CD4 + T cells, but not monocyte-derived dendritic cells. Retrovirology 12: 2.
Laguette N., Sobhian B., Casartelli N., Ringeard M., Chable-Bessia C., Ségéral E., Yatim A., Emiliani S., Schwartz O. and Benkirane M. 2011. SAMHD1 is the dendritic and myeloid cell-specific HIV-1 restriction factor that Vpx counteracts. Nature 474, 654- 7th
Ayinde, D., N. Casartelli, and O. Schwartz. 2012. Limitation of the SAMHD1 pathway by HIV: due to a lack of nucleotides. Nat Rev Microbiol 10: 675-65; 80.
3) Placental formation and innate immune responses
High-risk pregnancies are common and can be caused by environmental and genetic factors. About 10 to 20% of women have a miscarriage in the first trimester of pregnancy, and 10% have premature birth. Genes involved in immune response, placental biology, coagulation, metabolism, and angiogenesis have been identified in pregnancy complications. Certain infections or inflammatory diseases have an adverse effect on the developing fetus. Congenital syndromes can occur as a result of maternal infection with pathogens called “TORCH”, including toxoplasma, listeria, treponem and viruses (mainly rubella, cytomegalovirus, herpes, varicella zoster, HIV, West Nile virus and ZIKV, among others). An abnormal syncytiotrophoblast (ST) is seen during TORCH infections and other complications such as preeclampsia, genetic and autoimmune interferonopathies such as Aicardi-Goutières syndrome and systemic lupus erythematosus. The underlying mechanisms remain poorly characterized. We recently reported that type I interferon upregulates IFITM in cytotrophoblasts, blocking syncytin-mediated cell fusion and ST formation. Our results provide a molecular explanation for pregnancy complications associated with high IFN levels.
Ruigrok K., Vaney MC, Buchrieser J., Baquero E., Hellert J., Baron B., England P., Schwartz O., Rey FA, Backovic M. X-ray structures of the 6-helix bundle of human syncytins after fusion and their functional implications. J Mol Biol. 2019, December 6; 431 (24): 4922-4940. doi: 10.1016 / j.jmb.2019.10.020. Epub 2019, November 8th. PMID: 31711961.
Buchrieser J., Degrelle SA, Couderc T., Nevers Q., Disson O., Manet C., Donahue DA, Porrot F., Hillion KH, Perthame E., Arroyo MV, Souquere S., Ruigrok K., Dupressoir A ., Heidmann T., Montagutelli X., Fournier T., Lecuit M, Schwartz O. IFITM proteins inhibit the formation of placental syncytiotrophoblasts and promote fetal death. Science. 2019, July 12; 365 (6449): 176-180.
Full list of published work:
188 publications (23,500 citations, h-index 73, Google Scholar)
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