TY - JOUR
T1 - Patterns of the within-host evolution of human norovirus in immunocompromised individuals and implications for treatment
AU - Izquierdo-Lara, Ray W.
AU - Villabruna, Nele
AU - Hesselink, Dennis A.
AU - Schapendonk, Claudia M.E.
AU - Ribó Pons, Sol
AU - Nieuwenhuijse, David
AU - Meier, Jenny I.J.
AU - Goodfellow, Ian
AU - Dalm, Virgil A.S.H.
AU - Fraaij, Pieter L.A.
AU - van Kampen, Jeroen J.A.
AU - Koopmans, Marion P.G.
AU - de Graaf, Miranda
N1 - Publisher Copyright: © 2024 The Authors
PY - 2024/11
Y1 - 2024/11
N2 - Background: Currently, there is no licensed treatment for chronic norovirus infections, but the use of intra-duodenally-delivered immunoglobulins is promising; nevertheless, varying results have limited their wide use. Little is known about the relationship between norovirus genetic diversity and treatment efficacy. Methods: We analyzed the norovirus within-host diversity and evolution in a cohort of 20 immunocompromised individuals using next-generation sequencing (NGS) and clone-based sequencing of the capsid (VP1) gene. Representative VP1s were expressed and their glycan receptor binding affinity and antigenicity were evaluated. Findings: The P2 domain, within the VP1, accumulated up to 30-fold more non-synonymous mutations than other genomic regions. Intra-host virus populations in these patients tended to evolve into divergent lineages that were often antigenically distinct. Several of these viruses were widely resistant to binding-blocking antibodies in immunoglobulin preparations. Notably, for one patient, a single amino-acid substitution in the P2 domain resulted in an immune-escape phenotype, and it was likely the main contributor to treatment failure. Furthermore, we found evidence for transmission of late-stage viruses between two immunocompromised individuals. Interpretation: The findings demonstrated that within-host noroviruses in chronic infections tend to evolve into antigenically distinct subpopulations. This antigenic evolution was likely caused by the remaining low immunity levels exerted by immunocompromised individuals, possibly undermining antiviral treatment. Our observations provide insights into norovirus (within-host) evolution and treatment. Funding:Erasmus MC grant mRACE, the European Union'sHorizon 2020 research and innovation program under grant agreement No. 874735 (VEO), and the NWO STEVIN award (Koopmans).
AB - Background: Currently, there is no licensed treatment for chronic norovirus infections, but the use of intra-duodenally-delivered immunoglobulins is promising; nevertheless, varying results have limited their wide use. Little is known about the relationship between norovirus genetic diversity and treatment efficacy. Methods: We analyzed the norovirus within-host diversity and evolution in a cohort of 20 immunocompromised individuals using next-generation sequencing (NGS) and clone-based sequencing of the capsid (VP1) gene. Representative VP1s were expressed and their glycan receptor binding affinity and antigenicity were evaluated. Findings: The P2 domain, within the VP1, accumulated up to 30-fold more non-synonymous mutations than other genomic regions. Intra-host virus populations in these patients tended to evolve into divergent lineages that were often antigenically distinct. Several of these viruses were widely resistant to binding-blocking antibodies in immunoglobulin preparations. Notably, for one patient, a single amino-acid substitution in the P2 domain resulted in an immune-escape phenotype, and it was likely the main contributor to treatment failure. Furthermore, we found evidence for transmission of late-stage viruses between two immunocompromised individuals. Interpretation: The findings demonstrated that within-host noroviruses in chronic infections tend to evolve into antigenically distinct subpopulations. This antigenic evolution was likely caused by the remaining low immunity levels exerted by immunocompromised individuals, possibly undermining antiviral treatment. Our observations provide insights into norovirus (within-host) evolution and treatment. Funding:Erasmus MC grant mRACE, the European Union'sHorizon 2020 research and innovation program under grant agreement No. 874735 (VEO), and the NWO STEVIN award (Koopmans).
UR - http://www.scopus.com/inward/record.url?scp=85205964543&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2024.105391
DO - 10.1016/j.ebiom.2024.105391
M3 - Article
C2 - 39396425
AN - SCOPUS:85205964543
SN - 2352-3964
VL - 109
JO - EBioMedicine
JF - EBioMedicine
M1 - 105391
ER -