Viral Genetic Determinants of Prolonged Respiratory Syncytial Virus Infection Among Infants in a Healthy Term Birth Cohort.

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 (Padj = .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.
Competing Interests: Potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Funding for this work has been supplied by the NIH and the SNSF. Funding to pay the Open Access publication charges for this article was provided by NIH. Tina Hartert; consulting fees: Sanofi Pasteur scientific advisory board RSV vaccines, participation on a data safety monitoring board: Pfizer. Larry J. Anderson; Grants or contracts (exlcuding funding for this project): CDC contract for herpes simplex antibody testing, subcontract with Sciogen on an NIH SBIR for RSV vaccines, contract with Pfizer to serologic testing studies of RSV, consulting fees: Janssen scientific advisory board RSV vaccines, ADVI scientific advisory board RSV vaccines, and Bavarian Nordic scientific advisory board, patents planned, issued or pending: RSV vaccines and Immune treatment, and RSV VLP vaccines.
(© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)