Background. Respiratory syncytial virus (RSV) is associated with acute respiratory infection. We sought to identify RSV variants associated with prolonged infection.

Methods. Among healthy term infants we identified those with prolonged RSV infection and conducted (1) a human genome-wide association study (GWAS) to test the dependence of infection risk on host genotype, (2) a viral GWAS for association with prolonged RSV infection using RSV whole-genome sequencing, (3) an analysis of all viral public sequences, (4) an assessment of immunological responses, and (5) a summary of all major functional data. Analyses were adjusted for viral/human population structure and host factors associated with infection risk.

Results. We identified p.E123K/D and p.P218T/S/L in G protein that were associated with prolonged infection (P-adj = .01). We found no evidence of host genetic risk for infection. The RSV variant positions approximate sequences that could bind a putative viral receptor, heparan sulfate.

Conclusions. Using analysis of both viral and host genetics we identified a novel RSV variant associated with prolonged infection in otherwise healthy infants and no evidence supporting host genetic susceptibility to infection. As the capacity of RSV for chronicity and its viral reservoir are not defined, these findings are important for understanding the impact of RSV on chronic disease and endemicity.