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.
View: Text | PDF
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

×

Figure 2

Maximum allele frequency plots for nonsynonymous mutational changes across the whole genome during persistent HPIV3 infection.

Options: View larger image (or click on image) Download as PowerPoint
Maximum allele frequency plots for nonsynonymous mutational changes acro...
Maximum allele frequency noted for nonsynonymous mutational changes across whole genome during persistent HPIV3 infection for patient 1 (A) and patient 2 (B). All changes are relative to the day 0 majority consensus for each patient. Mutational changes were determined using LAVA. Plots show nonsynonymous mutations present in at least 2 longitudinal time points that had minor allele frequency more than 5% and depth more than 10 reads and passed manual review for tagmentation artifacts. Nucleotide position is listed across the x axis and maximum allele frequency observed is plotted on the y axis. Alternating green and blue rectangles denote protein coding regions. Mutational changes observed in the HN protein and those above 50% maximum allele frequency are labeled with consensus amino acid, amino acid position relative to protein start, and amino acid change.