Whole-Genome Next-Generation Sequencing to Study Within-Host Evolution of Norovirus (NoV) among Immunocompromised Patients with Chronic NoV Infection

Background. The genus Norovirus comprises large genetic diversity, and new GII.4 variants emerge every 2-3 years. It is unknown in which host these new variants originate. Here we study whether prolonged shedders within the immunocompromised population could be a reservoir for newly emerging strains. Methods. Sixty-five fecal samples from 16 immunocompromised patients were retrospectively selected. Isolated viral RNA was enriched by hybridization with a custom norovirus whole-genome RNA bait set and deep sequenced on the Illumina MiSeq platform. Results. Patients shed virus for average 352 days (range, 76-716 days). Phylogenetic analysis showed distinct GII.4 variants in 3 of 13 patients (23%). The viral mutation rates were variable between patients but did not differ between various immune status groups. All within-host GII.4 viral populations showed amino acid changes at blocking epitopes over time, and the majority of VP1 amino acid mutations were located at the capsid surface. Conclusions. This study found viruses in immunocompromised hosts that are genetically distinct from viruses circulating in the general population, and these patients therefore may contain a reservoir for newly emerging strains. Future studies need to determine whether these new strains are of risk to other immunocompromised patients and the general population.

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