Deep sequencing of RSV from an adult challenge study and from naturally infected infants reveals heterogeneous diversification dynamics

Abstract

As RNA virus mutation occurs during replication within host cells, we hypothesized that viral evolution during acute infections in healthy hosts reflects host immune pressure. We therefore investigated the within-host diversification of human respiratory syncytial virus (RSV), a highly prevalent cause of acute respiratory infections. We evaluated healthy adults experimentally infected with an identical inoculum and infants hospitalized with naturally acquired infections. In aggregate, viral diversification in adults peaked at day 3, with overrepresentation of diversity in the matrix protein 2 (M2) and non-structural protein 2 (NS2) genes. In one subject, delayed viral clearance was accompanied by a late peak of diversity at day 10 in known and predicted B and T cell epitopes. In contrast, infant infections showed much less viral diversity. Our findings suggest multiple overlapping mechanisms for early control of acute viral infections, which may differ between age groups and host immune responses.

Distinct patterns of within-host virus populations between two subgroups of human respiratory syncytial virus

“…A previous study showed that within-host RSV diversity increased in an immunocompromised infant with persistent RSV infection following a haematopoietic stem cell transplant, and palivizumab escape mutants emerged after multiple administrations of this drug 21 . Another study demonstrated that RSV-A exhibited greater within-host virus diversity in experimentally infected adults than in naturally infected infants 22 . However, these results were limited to RSV-A infection and did not look at natural infections in adult populations.…”

A Randomized, Placebo-Controlled, Respiratory Syncytial Virus Human Challenge Study of the Antiviral Efficacy, Safety, and Pharmacokinetics of RV521, an Inhibitor of the RSV-F Protein

“…The detected G453D and P389L RSV-F protein variants have not been reported to reduce susceptibility to inhibitors of the RSV-F protein. However, P389L was detected in a placebo-treated RSV-A Memphis-37binfected subject in another virus challenge study (personal communication, Y. H. Grad) (24), and therefore its occurrence in our study most likely resulted from natural variation rather than from RV521 treatment. Findings from the mutation analysis conducted during our clinical study compare favorably with those reported for GS-5806, in which treatment-emergent mutations conferring reduced susceptibility in vitro to GS-5806 were detected in 14 of 87 subjects treated with the agent and challenged with RSV (and in 0 of 53 placebo-treated subjects) (22).…”

Drivers of within-host genetic diversity in acute infections of viruses

“…For RSV samples, apart from possibly a single sample we found no evidence for multiple haplotypes in the samples, which is somewhat surprising given that this is an airborne virus that reaches high titers. Previous work has suggested that the number of founders in RSV infections is 25±35 [ 38 ]. Notably, these values were obtained for adults experimentally inoculated with RSV, whereas our study represent natural infection of infants.…”