Human parainfluenza virus evolution during lung infection of immunocompromised individuals promotes viral persistence
Alexander L. Greninger, … , Matteo Porotto, Anne Moscona
Alexander L. Greninger, … , Matteo Porotto, Anne Moscona
Published October 5, 2021
Citation Information: J Clin Invest. 2021;131(23):e150506. https://doi.org/10.1172/JCI150506.
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Research Article Virology

Human parainfluenza virus evolution during lung infection of immunocompromised individuals promotes viral persistence

Abstract

The capacity of respiratory viruses to undergo evolution within the respiratory tract raises the possibility of evolution under the selective pressure of the host environment or drug treatment. Long-term infections in immunocompromised hosts are potential drivers of viral evolution and development of infectious variants. We showed that intrahost evolution in chronic human parainfluenza virus 3 (HPIV3) infection in immunocompromised individuals elicited mutations that favored viral entry and persistence, suggesting that similar processes may operate across enveloped respiratory viruses. We profiled longitudinal HPIV3 infections from 2 immunocompromised individuals that persisted for 278 and 98 days. Mutations accrued in the HPIV3 attachment protein hemagglutinin-neuraminidase (HN), including the first in vivo mutation in HN’s receptor binding site responsible for activating the viral fusion process. Fixation of this mutation was associated with exposure to a drug that cleaves host-cell sialic acid moieties. Longitudinal adaptation of HN was associated with features that promote viral entry and persistence in cells, including greater avidity for sialic acid and more active fusion activity in vitro, but not with antibody escape. Long-term infection thus led to mutations promoting viral persistence, suggesting that host-directed therapeutics may support the evolution of viruses that alter their biophysical characteristics to persist in the face of these agents in vivo.

Authors

Alexander L. Greninger, Ksenia Rybkina, Michelle J. Lin, Jennifer Drew-Bear, Tara C. Marcink, Ryan C. Shean, Negar Makhsous, Michael Boeckh, Olivia Harder, Francesca Bovier, Shana R. Burstein, Stefan Niewiesk, Bert K. Rima, Matteo Porotto, Anne Moscona

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Figure 1

Longitudinal sampling of long-term HPIV3 infections in vivo.

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Longitudinal sampling of long-term HPIV3 infections in vivo. Sampling ti...
Sampling time series data with associated Ct values shown for patient 1 (A) and patient 2 (B). Samples collected by nasal swabs are represented by dots; black dots are HPIV3-positive samples with associated sequencing data, gray dots are HPIV3-positive samples that were not available for sequencing, and empty dots tested negative for HPIV3. HPIV3-positive bronchoalveolar lavage (BAL) samples are represented by asterisks. Light blue boxes indicate time periods in which patient 1 was treated with DAS181. Amino acid sequences of the HN protein for patient 1 and patient 2 are placed in the context of circulating strains that were downloaded from NCBI’s GenBank (C). All sequences are labeled with GenBank accession number followed by collection location and collection date. Consensus support values are shown next to branch points. The laboratory-adapted HPIV3 reference strain (NC_001796) is used as an outgroup. Amino acid alignment of the day 0 consensus sequences of the HN and F attachment proteins for each patient were aligned with the clinical isolate used in functional assays (D). Only amino acids that differ among these isolates are depicted.