SARS-CoV-2 evolution during treatment of chronic infection.

Autor: Kemp SA; Division of Infection and Immunity, University College London, London, UK., Collier DA; Division of Infection and Immunity, University College London, London, UK.; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.; Department of Medicine, University of Cambridge, Cambridge, UK., Datir RP; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.; Department of Medicine, University of Cambridge, Cambridge, UK., Ferreira IATM; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.; Department of Medicine, University of Cambridge, Cambridge, UK., Gayed S; Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, Cambridge, UK., Jahun A; Department of Pathology, University of Cambridge, Cambridge, UK., Hosmillo M; Department of Pathology, University of Cambridge, Cambridge, UK., Rees-Spear C; Division of Infection and Immunity, University College London, London, UK., Mlcochova P; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.; Department of Medicine, University of Cambridge, Cambridge, UK., Lumb IU; NHS Blood and Transplant, Oxford and BRC Haematology Theme, University of Oxford, Oxford, UK., Roberts DJ; NHS Blood and Transplant, Oxford and BRC Haematology Theme, University of Oxford, Oxford, UK., Chandra A; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.; Department of Medicine, University of Cambridge, Cambridge, UK., Temperton N; Viral Pseudotype Unit, Medway School of Pharmacy, University of Kent, Canterbury, UK., Sharrocks K; Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, Cambridge, UK., Blane E; Department of Medicine, University of Cambridge, Cambridge, UK., Modis Y; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.; Department of Medicine, University of Cambridge, Cambridge, UK.; Medical Research Council Laboratory of Molecular Biology, Cambridge, UK., Leigh KE; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.; Department of Medicine, University of Cambridge, Cambridge, UK.; Medical Research Council Laboratory of Molecular Biology, Cambridge, UK., Briggs JAG; Medical Research Council Laboratory of Molecular Biology, Cambridge, UK., van Gils MJ; Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands., Smith KGC; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.; Department of Medicine, University of Cambridge, Cambridge, UK., Bradley JR; Department of Medicine, University of Cambridge, Cambridge, UK.; NIHR Cambridge Bioresource, Cambridge, UK., Smith C; Department of Virology, Cambridge University NHS Hospitals Foundation Trust, Cambridge, UK., Doffinger R; Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, UK., Ceron-Gutierrez L; Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, UK., Barcenas-Morales G; Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, UK.; FES-Cuautitlán, UNAM, Cuautitlán Izcalli, Mexico., Pollock DD; Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA., Goldstein RA; Division of Infection and Immunity, University College London, London, UK., Smielewska A; Department of Pathology, University of Cambridge, Cambridge, UK.; Department of Virology, Cambridge University NHS Hospitals Foundation Trust, Cambridge, UK., Skittrall JP; Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, Cambridge, UK.; Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK.; Clinical Microbiology and Public Health Laboratory, Addenbrooke's Hospital, Cambridge, UK., Gouliouris T; Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, Cambridge, UK., Goodfellow IG; Department of Pathology, University of Cambridge, Cambridge, UK., Gkrania-Klotsas E; Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, Cambridge, UK., Illingworth CJR; Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK.; MRC Biostatistics Unit, University of Cambridge, Cambridge, UK., McCoy LE; Division of Infection and Immunity, University College London, London, UK., Gupta RK; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK. rkg20@cam.ac.uk.; Department of Medicine, University of Cambridge, Cambridge, UK. rkg20@cam.ac.uk.; Africa Health Research Institute, Durban, South Africa. rkg20@cam.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Apr; Vol. 592 (7853), pp. 277-282. Date of Electronic Publication: 2021 Feb 05.
DOI: 10.1038/s41586-021-03291-y
Abstrakt: 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 protein 1 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.
Databáze: MEDLINE
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