Human parainfluenza virus evolution during lung infection of immunocompromised individuals promotes viral persistence
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
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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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 5

Patient-derived HPIV3 HN proteins have altered receptor-binding and receptor-cleaving properties.

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Patient-derived HPIV3 HN proteins have altered receptor-binding and rece...
(A) Neuraminidase activity of patient-derived HPIV3 HNs. HEK293T cells were transfected with plasmids containing corresponding sequences of clinically isolated HNs. Neuraminidase activity was quantified by measuring amount of cleavage of 4-MUNANA. Results depict representative experiments from 3 biological replicates. Data indicate the mean ± SD. A 1-way ANOVA was performed to determine significance; P values are specified as follows: *P ≤ 0.05; ****P ≤ 0.0001. FC, fold change. (B) Release kinetics of patient-derived HPIV3 HNs binding sialic acid–containing RBCs at 37°C. HEK293T cells transiently expressing HNs were incubated with RBCs at 4°C for 30 minutes, washed, and transferred to 37°C. Supernatant was collected at 0, 5, 10, 15, 45, and 60 minutes and percentage of RBCs released at each time point was determined by quantification of relative absorbance at 410 nm. Results depict representative experiments from 3 biological replicates.