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SUMMARY:Replication of SARS-CoV-2 variants and  host immune responses
DESCRIPTION:Please join us for the latest instalment of the Wright-Fleming 
 Institute\,\nInfection and Immunity Seminar Series\nProfessor Olivier Schw
 artz\nThe long-lasting interest of our laboratory is the study of the mole
 cular and cellular mechanisms regulating viral replication and interaction
  with the host. We are studying HIV\, Chikungunya virus\, Zika virus and m
 ore 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 ste
 ps of the viral life cycle. We are also studying how the humoral immune re
 sponse controls viral replication.\n\nContributions to Science\n1) Activit
 y of non-neutralizing and broadly neutralizing (bNAbs) anti-HIV-1 antibodi
 es\n We identified a subset of bNAbs that inhibit both cell-free and cell
 -mediated infection in primary CD4+ lymphocytes. These antibodies accumula
 te at virological synapses and impair the clustering and fusion of infecte
 d and target cells and the transfer of viral material to uninfected T cell
 s. In addition\, they block viral cell-to-cell transmission to pDCs and th
 ereby interfere with type-I IFN production.\nWe also characterized bNAbs t
 hat exert Antibody-dependent cellular cytotoxicity in culture and kill HIV
 -1-infected lymphocytes through NK engagement. The landscape of Env epitop
 e exposure at the surface and the sensitivity of infected cells to ADCC va
 ry considerably between viral strains. Efficient ADCC requires sustained c
 ell surface binding of bNAbs to Env\, and combining bNAbs allows a potent 
 killing activity. Furthermore\, reactivated infected cells from HIV-positi
 ve individuals expose heterogeneous Env epitope patterns\, with levels tha
 t are often but not always sufficient to trigger killing by bNAbs. Our stu
 dy delineated the parameters controlling ADCC activity of bNAbs\, and supp
 orts the use of the most potent antibodies to clear the viral reservoir.\n
  Main publications\nDufloo J\, Bruel T\, Schwartz O HIV-1 cell-to-cell tr
 ansmission and broadly neutralizing antibodies. Retrovirology. 2018 Jul 28
 \;15(1):51.\nBruel T\, Guivel-Benhassine F\, Amraoui S\, Malbec M\, Richar
 d L\, Bourdic K\, Donahue DA\, Lorin V\, Casartelli N\, Noël N\, Lambotte
  O\, Mouquet H\, Schwartz O. Elimination of HIV-1 infected cells by broadl
 y neutralizing antibodies. Nature Communications\, 2016 Mar 3\;7:10844. do
 i: 10.1038/ncomms10844.\nMalbec M\, Porrot F\, Rua R\, Horwitz J\, Klein F
 \, Halper-Stromberg A\, Scheid J\, Eden C\, Mouquet H\, Nussenzweig MC\, S
 chwartz O. 2013. Broadly neutralizing antibodies that inhibit HIV-1 cell-t
 o-cell transmission. J. Exp. Med. Dec 16\;210(13):2813-21.\n2) HIV\, dendr
 itic cells and macrophages\, role of SAMHD1\n 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 r
 esting CD4+ T cells\, but does not confer HIV-2 with the ability to effici
 ently 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 avo
 id triggering an immune response mediated by these cells. We further showe
 d that MDDCs are poorly sensitive to HIV-1 and HIV-2 infection\, because o
 f low cell surface levels of CD4.\nWe examined the consequences of the ant
 iviral 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.\n Main publications\nChauvea
 u 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.
 \nChauveau 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.\nLague
 tte N\, Sobhian B\, Casartelli N\, Ringeard M\, Chable-Bessia C\, Ségéra
 l E\, Yatim A\, Emiliani S\, Schwartz O\, and Benkirane M. 2011. SAMHD1 is
  the dendritic- and myeloid-cell-specific HIV-1 restriction factor counter
 acted by Vpx. Nature 474\, 654-7.\nAyinde\, D.\, N. Casartelli\, and O. Sc
 hwartz. 2012. Restricting HIV the SAMHD1 way: through nucleotide starvatio
 n. Nat Rev Microbiol 10:675-80.\n3) Placenta formation and innate immune r
 esponses\nHigh-risk pregnancies occur frequently and may be caused by envi
 ronmental and genetic factors. About 10-20% of women miscarry during the f
 irst 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. Certa
 in infections or inflammatory conditions have detrimental effects on the d
 eveloping foetus. Congenital syndromes may arise as a result of maternal i
 nfection with pathogens termed “TORCH”\, including toxoplasma\, lister
 ia\, treponema and viruses\, (mainly Rubella\, Cytomegalovirus\, Herpes\, 
 Varicella Zoster\, HIV\, West Nile Virus and ZIKV\, among others). An abno
 rmal Syncytiotrophoblast (ST) is observed during TORCH infections and othe
 r complications including preeclampsia\, genetic and auto-immune interfero
 nopathies such as Aicardi-Goutières syndrome and systemic lupus erythema
 tosus. 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 wi
 th high levels of IFN.\nMain publications\nRuigrok K\, Vaney MC\, Buchries
 er 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 Hum
 an Syncytins and their Functional Implications. J Mol Biol. 2019 Dec 6\;43
 1(24):4922-4940. doi: 10.1016/ j.jmb.2019.10.020. Epub 2019 Nov 8. PMID: 3
 1711961.\nBuchrieser J\, Degrelle SA\, Couderc T\, Nevers Q\, Disson O\, M
 anet C\, Donahue DA\, Porrot F\, Hillion KH\, Perthame E\, Arroyo MV\, Sou
 quere S\, Ruigrok K\, Dupressoir A\, Heidmann T\, Montagutelli X\, Fournie
 r T\, Lecuit M\, Schwartz O. IFITM proteins inhibit placental syncytiotrop
 hoblast formation and promote fetal demise. Science. 2019 Jul 12\;365(6449
 ):176-180.\nComplete List of Published Work:\n188 publications\, (23\,500 
 citations\, h-index 73\, Google Scholar)\nhttps://scholar.google.com/citat
 ions?hl=fr&user=zclllwsAAAAJ&view_op=list_works&sortby=pubdate\n\nA record
 ing may be available for college users\, please refer to Teams/WFI seminar
  series listing page next day.  \nhttps://www.imperial.ac.uk/infectious-d
 isease/research/virology/wright-fleming-seminars \n\nJoin on your computer
  or mobile app\nClick here to join the meeting 
URL:https://www.imperial.ac.uk/events/130251/replication-of-sars-cov-2-vari
 ants-and-host-immune-responses/
DTSTART;TZID=Europe/London:20210223T123000
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LOCATION:United Kingdom
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