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The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.
SARS-CoV-2 evolution during treatment of chronic infection
Kemp S. A.;Collier D. A.;Datir R. P.;Ferreira I. A. T. M.;Gayed S.;Jahun A.;Hosmillo M.;Rees-Spear C.;Mlcochova P.;Lumb I. U.;Roberts D. J.;Chandra A.;Temperton N.;Baker S.;Dougan G.;Hess C.;Kingston N.;Lehner P. J.;Lyons P. A.;Matheson N. J.;Owehand W. H.;Saunders C.;Summers C.;Thaventhiran J. E. D.;Toshner M.;Weekes M. P.;Bucke A.;Calder J.;Canna L.;Domingo J.;Elmer A.;Fuller S.;Harris J.;Hewitt S.;Kennet J.;Jose S.;Kourampa J.;Meadows A.;O'Brien C.;Price J.;Publico C.;Rastall R.;Ribeiro C.;Rowlands J.;Ruffolo V.;Tordesillas H.;Bullman B.;Dunmore B. J.;Fawke S.;Graf S.;Hodgson J.;Huang C.;Hunter K.;Jones E.;Legchenko E.;Matara C.;Martin J.;Mescia F.;O'Donnell C.;Pointon L.;Pond N.;Shih J.;Sutcliffe R.;Tilly T.;Treacy C.;Tong Z.;Wood J.;Wylot M.;Bergamaschi L.;Betancourt A.;Bower G.;Cossetti C.;De Sa A.;Epping M.;Fawke S.;Gleadall N.;Grenfell R.;Hinch A.;Huhn O.;Jackson S.;Jarvis I.;Lewis D.;Marsden J.;Nice F.;Okecha G.;Omarjee O.;Perera M.;Richoz N.;Romashova V.;Yarkoni N. S.;Sharma R.;Stefanucci L.;Stephens J.;Strezlecki M.;Turner L.;De Bie E. M. D. D.;Bunclark K.;Josipovic M.;Mackay M.;Rossi S.;Selvan M.;Spencer S.;Yong C.;Ansaripour A.;Michael A.;Mwaura L.;Patterson C.;Polwarth G.;Polgarova P.;di Stefano G.;Fahey C.;Michel R.;Bong S. -H.;Coudert J. D.;Holmes E.;Allison J.;Butcher H.;Caputo D.;Clapham-Riley D.;Dewhurst E.;Furlong A.;Graves B.;Gray J.;Ivers T.;Kasanicki M.;Le Gresley E.;Linger R.;Meloy S.;Muldoon F.;Ovington N.;Papadia S.;Phelan I.;Stark H.;Stirrups K. E.;Townsend P.;Walker N.;Webster J.;Robson S. C.;Loman N. J.;Connor T. R.;Golubchik T.;Martinez Nunez R. T.;Ludden C.;Corden S.;Johnston I.;Bonsall D.;Smith C. P.;Awan A. R.;Bucca G.;Estee Torok M.;Saeed K.;Prieto J. A.;Jackson D. K.;Hamilton W. L.;Snell L. B.;Moore C.;Harrison E. M.;Goncalves S.;Fairley D. J.;Loose M. W.;Watkins J.;Livett R.;Moses S.;Amato R.;Nicholls S.;Bull M.;Smith D. L.;Barrett J.;Aanensen D. M.;Curran M. D.;Parmar S.;Aggarwal D.;Shepherd J. G.;Parker M. D.;Glaysher S.;Bashton M.;Underwood A. P.;Pacchiarini N.;Loveson K. F.;Carabelli A. M.;Templeton K. E.;Langford C. F.;Sillitoe J.;de Silva T. I.;Wang D.;Kwiatkowski D.;Rambaut A.;O'Grady J.;Cottrell S.;Holden M. T. G.;Thomson E. C.;Osman H.;Andersson M.;Chauhan A. J.;Hassan-Ibrahim M. O.;Lawniczak M.;Alderton A.;Chand M.;Constantinidou C.;Unnikrishnan M.;Darby A. C.;Hiscox J. A.;Paterson S.;Martincorena I.;Robertson D. L.;Volz E. M.;Page A. J.;Pybus O. G.;Bassett A. R.;Ariani C. V.;Spencer Chapman M. H.;Li K. K.;Shah R. N.;Jesudason N. G.;Taha Y.;McHugh M. P.;Dewar R.;Jahun A. S.;McMurray C.;Pandey S.;McKenna J. P.;Nelson A.;Young G. R.;McCann C. M.;Elliott S.;Lowe H.;Temperton B.;Roy S.;Price A.;Rey S.;Wyles M.;Rooke S.;Shaaban S.;de Cesare M.;Letchford L.;Silveira S.;Pelosi E.;Wilson-Davies E.;Hosmillo M.;O'Toole A.;Hesketh A. R.;Stark R.;du Plessis L.;Ruis C.;Adams H.;Bourgeois Y.;Michell S. L.;Gramatopoulos D.;Edgeworth J.;Breuer J.;Todd J. A.;Fraser C.;Buck D.;John M.;Kay G. 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J.;Drury E.;Kane L.;Kay S.;McGuigan S.;Nelson R.;Prestwood L.;Rajatileka S.;Batra R.;Williams R. J.;Kristiansen M.;Green A.;Justice A.;Mahanama A. I. K.;Samaraweera B.;Hadjirin N. F.;Quick J.;Poplawski R.;Kermack L. M.;Reynolds N.;Hall G.;Chaudhry Y.;Pinckert M. L.;Georgana I.;Moll R. J.;Thornton A.;Myers R.;Stockton J.;Williams C. A.;Yew W. C.;Trotter A. J.;Trebes A.;MacIntyre-Cockett G.;Birchley A.;Adams A.;Plimmer A.;Gatica-Wilcox B.;McKerr C.;Hilvers E.;Jones H.;Asad H.;Coombes J.;Evans J. M.;Fina L.;Gilbert L.;Graham L.;Cronin M.;Kumziene-Summerhayes S.;Taylor S.;Jones S.;Groves D. C.;Zhang P.;Gallis M.;Louka S. F.;Starinskij I.;Jackson C.;Gourtovaia M.;Tonkin-Hill G.;Lewis K.;Tovar-Corona J. M.;James K.;Baxter L.;Alam M. T.;Orton R. J.;Hughes J.;Vattipally S.;Ragonnet-Cronin M.;Nascimento F. F.;Jorgensen D.;Boyd O.;Geidelberg L.;Zarebski A. E.;Raghwani J.;Kraemer M. U. G.;Southgate J.;Lindsey B. B.;Freeman T. M.;Keatley J. -P.;Singer J. B.;de Oliveira Martins L.;Yeats C. A.;Abudahab K.;Taylor B. E. W.;Menegazzo M.;Danesh J.;Hogsden W.;Eldirdiri S.;Kenyon A.;Mason J.;Robinson T. I.;Holmes A.;Price J.;Hartley J. A.;Curran T.;Mather A. E.;Shankar G.;Jones R.;Howe R.;Morgan S.;Wastenge E.;Chapman M. R.;Mookerjee S.;Stanley R.;Smith W.;Peto T.;Eyre D.;Crook D.;Vernet G.;Kitchen C.;Gulliver H.;Merrick I.;Guest M.;Munn R.;Bradley D. T.;Wyatt T.;Beaver C.;Foulser L.;Palmer S.;Churcher C. M.;Brooks E.;Smith K. S.;Galai K.;McManus G. M.;Bolt F.;Coll F.;Meadows L.;Attwood S. W.;Davies A.;De Lacy E.;Downing F.;Edwards S.;Scarlett G. P.;Jeremiah S.;Smith N.;Leek D.;Sridhar S.;Forrest S.;Cormie C.;Gill H. K.;Dias J.;Higginson E. E.;Maes M.;Young J.;Wantoch M.;Jamrozy D.;Lo S.;Patel M.;Hill V.;Bewshea C. M.;Ellard S.;Auckland C.;Harrison I.;Bishop C.;Chalker V.;Richter A.;Beggs A.;Best A.;Percival B.;Mirza J.;Megram O.;Mayhew M.;Crawford L.;Ashcroft F.;Moles-Garcia E.;Cumley N.;Hopes R.;Asamaphan P.;Niebel M. O.;Gunson R. 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2021-01-01
Abstract
The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11379/562816
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simulazione ASN
Il report seguente simula gli indicatori relativi alla propria produzione scientifica in relazione alle soglie ASN 2023-2025 del proprio SC/SSD. Si ricorda che il superamento dei valori soglia (almeno 2 su 3) è requisito necessario ma non sufficiente al conseguimento dell'abilitazione. La simulazione si basa sui dati IRIS e sugli indicatori bibliometrici alla data indicata e non tiene conto di eventuali periodi di congedo obbligatorio, che in sede di domanda ASN danno diritto a incrementi percentuali dei valori. La simulazione può differire dall'esito di un’eventuale domanda ASN sia per errori di catalogazione e/o dati mancanti in IRIS, sia per la variabilità dei dati bibliometrici nel tempo. Si consideri che Anvur calcola i valori degli indicatori all'ultima data utile per la presentazione delle domande.
La presente simulazione è stata realizzata sulla base delle specifiche raccolte sul tavolo ER del Focus Group IRIS coordinato dall’Università di Modena e Reggio Emilia e delle regole riportate nel DM 589/2018 e allegata Tabella A. Cineca, l’Università di Modena e Reggio Emilia e il Focus Group IRIS non si assumono alcuna responsabilità in merito all’uso che il diretto interessato o terzi faranno della simulazione. Si specifica inoltre che la simulazione contiene calcoli effettuati con dati e algoritmi di pubblico dominio e deve quindi essere considerata come un mero ausilio al calcolo svolgibile manualmente o con strumenti equivalenti.
