Abstract
Human noroviruses (NVs) are the leading cause of acute gastroenteritis outbreaks worldwide. The majority of outbreaks are caused by genogroup II.4 (GII.4), with new variants emerging every 2 to 4 years. Immunocompromised patients are hypothesized to be important reservoirs where new NV variants emerge. Here, we examined intra-host NV variants and assessed immune-driven NV evolution in chronically infected immunocompromised hosts. Three NV GII.4-positive samples were collected from the same patient in different clinical phases following allogeneic hematopoietic stem cell transplantation, and had viral RNA concentrations of 2.46 × 106, 1.47 × 106, and 2.26 × 106 genome copies/mL. The non-synonymous (dN) and synonymous (dS) substitution ratio of the sequences in the partial P domain were >1, indicating strong positive selection in the patient. Both the number and the frequency of the single nucleotide variants increased over time in the patient. Also, the majority of capsid amino acid changes were located at blocking epitopes and histo-blood group antigen (HBGA)-binding sites, and 11 positive selection sites were found in the capsid region, of which 8 sites were presented in blocking epitopes or HBGA-binding sites. Homodimeric P-domain capsid models also suggested a structural change in the epitopes and HBGA-binding sites. The results suggested that novel variants of NV GII.4 with HBGA and antigenic site changes were produced in the immunocompromised patient. Further functional and epidemiological studies are needed to determine whether the new variants are a risk to public health.
Highlights
Noroviruses (NVs) are the leading pathogens necessitating community and outpatient visits for acute gastroenteritis (Tam et al, 2012), and are the leading cause of gastroenteritis outbreaks worldwide, causing approximately half of all such outbreaks (Glass et al, 2009)
To evaluate NV evolution during chronic infection, we present a case of prolonged NV infection in a patient following hematopoietic stem cell transplantation (HSCT)
NV persistence in the human population is driven by viral evolution that results in antigenic drift and changes in binding characteristics to escape herd immunity
Summary
Noroviruses (NVs) are the leading pathogens necessitating community and outpatient visits for acute gastroenteritis (Tam et al, 2012), and are the leading cause of gastroenteritis outbreaks worldwide, causing approximately half of all such outbreaks (Glass et al, 2009). NV infections typically result in acute and self-limiting gastroenteritis, young children, the elderly people and immunocompromised patients are vulnerable to more severe and prolonged infections. Immuno-incompetent and transplant patients can be chronically infected with NVs. NVs are small, non-enveloped viruses with a genome of 7500 nucleotides (nt) of single positivestranded RNA. The genome is organized into three open reading frames (ORFs). ORF1 is translated as a polyprotein that is cleaved into six non-structural proteins, while ORF2 and ORF3 encode the major capsid protein (VP1) and minor capsid protein (VP2), respectively
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