Prof Olivier Schwartz

Please join us for the latest instalment of the Wright-Fleming Institute,
Infection and Immunity Seminar Series

Professor Olivier Schwartz

The long-lasting interest of our laboratory is the study of the molecular and cellular mechanisms regulating viral replication and interaction with the host. We are studying HIV, Chikungunya virus, Zika virus and more recently SARS-CoV-2. We are assessing the role of restriction factors, cellular proteins often induced by IFN and thus essential components of the host innate immunity, which inhibit viral replication at discrete steps of the viral life cycle. We are also studying how the humoral immune response controls viral replication.

Contributions to Science
1) Activity of non-neutralizing and broadly neutralizing (bNAbs) anti-HIV-1 antibodies
 We identified a subset of bNAbs that inhibit both cell-free and cell-mediated infection in primary CD4+ lymphocytes. These antibodies accumulate at virological synapses and impair the clustering and fusion of infected and target cells and the transfer of viral material to uninfected T cells. In addition, they block viral cell-to-cell transmission to pDCs and thereby interfere with type-I IFN production.
We also characterized bNAbs that exert Antibody-dependent cellular cytotoxicity in culture and kill HIV-1-infected lymphocytes through NK engagement. The landscape of Env epitope exposure at the surface and the sensitivity of infected cells to ADCC vary considerably between viral strains. Efficient ADCC requires sustained cell surface binding of bNAbs to Env, and combining bNAbs allows a potent killing activity. Furthermore, reactivated infected cells from HIV-positive individuals expose heterogeneous Env epitope patterns, with levels that are often but not always sufficient to trigger killing by bNAbs. Our study delineated the parameters controlling ADCC activity of bNAbs, and supports the use of the most potent antibodies to clear the viral reservoir.
 Main publications
Dufloo J, Bruel T, Schwartz O HIV-1 cell-to-cell transmission and broadly neutralizing antibodies. Retrovirology. 2018 Jul 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 broadly neutralizing antibodies. Nature Communications, 2016 Mar 3;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 that inhibit HIV-1 cell-to-cell transmission. J. Exp. Med. Dec 16;210(13):2813-21.
2) HIV, dendritic cells and macrophages, role of SAMHD1
We studied the interactions between HIV-1/HIV-2 and dendritic cells and macrophages. We reported that HIV-2 Vpx, by degrading SAMHD1, allows the non-productive infection of resting CD4+ T cells, but does not confer HIV-2 with the ability to efficiently infect macrophages. In these cells, an entry defect prevents viral fusion and reverse transcription independently of SAMHD1. We proposed that HIV-2, like HIV-1, does not productively infect MDDCs, possibly to avoid triggering an immune response mediated by these cells. We further showed that MDDCs are poorly sensitive to HIV-1 and HIV-2 infection, because of low cell surface levels of CD4.
We examined the consequences of the antiviral activity of SAMHD1 on HIV-1 antigen presentation and innate sensing in MDDCs. We showed that SAMHD1 restricts HIV-1 cell-to-cell transmission and limits immune detection in these cells.
 Main publications
Chauveau L, Donahue DA, Monel B, Porrot F, Bruel T, Richard L, Casartelli N, Schwartz O. HIV fusion in Dendritic cells mainly occurs at 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 resting 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 counteracted by Vpx. Nature 474, 654-7.
Ayinde, D., N. Casartelli, and O. Schwartz. 2012. Restricting HIV the SAMHD1 way: through nucleotide starvation. Nat Rev Microbiol 10:675-80.
3) Placenta formation and innate immune responses
High-risk pregnancies occur frequently and may be caused by environmental and genetic factors. About 10-20% of women miscarry during the first trimester of pregnancy and 10% will experience pre-term birth. Genes involved in immune response, placental biology, coagulation, metabolism, and angiogenesis have been identified in pregnancy complications. Certain infections or inflammatory conditions have detrimental effects on the developing foetus. Congenital syndromes may arise as a result of maternal infection with pathogens termed “TORCH”, including toxoplasma, listeria, treponema and viruses, (mainly Rubella, Cytomegalovirus, Herpes, Varicella Zoster, HIV, West Nile Virus and ZIKV, among others). An abnormal Syncytiotrophoblast (ST) is observed during TORCH infections and other complications including preeclampsia, genetic and auto-immune 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, which blocks Syncytin-mediated cell fusion and ST formation.  Our results provide a molecular explanation for pregnancy complications associated with high levels of IFN.
Main publications
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 Post-fusion 6-Helix Bundle of the Human Syncytins and their Functional Implications. J Mol Biol. 2019 Dec 6;431(24):4922-4940. doi: 10.1016/ j.jmb.2019.10.020. Epub 2019 Nov 8. 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 placental syncytiotrophoblast formation and promote fetal demise. Science. 2019 Jul 12;365(6449):176-180.
Complete List of Published Work:
188 publications, (23,500 citations, h-index 73, Google Scholar)

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