Within-host evolutionary dynamics of seasonal and pandemic human influenza A viruses in young children
- Amsterdam University Medical Center, Netherlands
- National Institute of Hygiene and Epidemiology, Viet Nam
- National Institute Of Hygiene And Epidemiology, Viet Nam
- Ha Nam Centre for Disease Control, Viet Nam
- Children's Hospital 2, Viet Nam
- Children's Hospital 1, Viet Nam
- Vietnam National Children's Hospital, Viet Nam
- Mahidol University, Thailand
- Hospital for Tropical Diseases, Viet Nam
- National Hospital for Tropical Diseases, Viet Nam
- Radboud University, Netherlands
- University of Oxford, United Kingdom
- University of Melbourne, Australia
Abstract
The evolution of influenza viruses is fundamentally shaped by within-host processes. However, the within-host evolutionary dynamics of influenza viruses remain incompletely understood, in part because most studies have focused on infections in healthy adults based on single timepoint data. Here, we analysed the within-host evolution of 82 longitudinally-sampled individuals, mostly young children, infected with A/H1N1pdm09 or A/H3N2 viruses between 2007 and 2009. For A/H1N1pdm09 infections during the 2009 pandemic, nonsynonymous minority variants were more prevalent than synonymous ones. For A/H3N2 viruses in young children, early infection was dominated by purifying selection. As these infections progressed, nonsynonymous variants typically increased in frequency even when within-host virus titres decreased. Unlike the short-lived infections of adults where de novo within-host variants are rare, longer infections in young children allow for the maintenance of virus diversity via mutation-selection balance creating potentially important opportunities for within-host virus evolution.
Data availability
All raw sequence data have been deposited at NCBI sequence read archive under BioProject Accession number PRJNA722099. All custom Python code and Jupyter notebooks to reproduce the analyses in this paper are available online: https://github.com/AMC-LAEB/Within_Host_H3vH1.
Article and author information
Author details
Zandra C Felix Garza
Matthijs RA Welkers
Funding
H2020 European Research Council (818353)
- Alvin X Han
- Zandra C Felix Garza
- Colin A Russell
National Institute of Allergy and Infectious Diseases (N01-A0-50042)
- Matthijs RA Welkers
- René M Vigeveno
- Nhu Duong Tran
- Thi Quynh Mai Le
- Thai Pham Quang
- Dinh Thoang Dang
- Thi Ngoc Anh Tran
- Manh Tuan Ha
- Thanh Hung Nguyen
- Quoc Thinh Le
- Thanh Hai Le
- Thi Bich Ngoc Hoang
- Kulkanya Chokephaibulkit
- Pilaipan Puthavathana
- Van Vinh Chau Nguyen
- My Ngoc Nghiem
- Van Kinh Nguyen
- Tuyet Trinh Dao
- Tinh Hien Tran
- Heiman FL Wertheim
- Peter W Horby
- Annette Fox
- H Rogier van Doorn
- Dirk Eggink
- Menno D de Jong
National Institutes of Health (HHSN272200500042C)
- Matthijs RA Welkers
- René M Vigeveno
- Nhu Duong Tran
- Thi Quynh Mai Le
- Thai Pham Quang
- Dinh Thoang Dang
- Thi Ngoc Anh Tran
- Manh Tuan Ha
- Thanh Hung Nguyen
- Quoc Thinh Le
- Thanh Hai Le
- Thi Bich Ngoc Hoang
- Kulkanya Chokephaibulkit
- Pilaipan Puthavathana
- Van Vinh Chau Nguyen
- My Ngoc Nghiem
- Van Kinh Nguyen
- Tuyet Trinh Dao
- Tinh Hien Tran
- Heiman FL Wertheim
- Peter W Horby
- Annette Fox
- H Rogier van Doorn
- Dirk Eggink
- Menno D de Jong
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The Institutional Review Board of all hospitals, the National Institute of Allergy and Infectious Diseases, and the Oxford Tropical Research Ethics Committee approved the study. Written informed consent was given by all patients (or proxies).
Copyright
© 2021, Han et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Within-host evolutionary dynamics of seasonal and pandemic human influenza A viruses in young children
eLife 10:e68917.
https://doi.org/10.7554/eLife.68917
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The majority of highly polymorphic genes are related to immune functions and with over 100 alleles within a population, genes of the major histocompatibility complex (MHC) are the most polymorphic loci in vertebrates. How such extraordinary polymorphism arose and is maintained is controversial. One possibility is heterozygote advantage (HA), which can in principle maintain any number of alleles, but biologically explicit models based on this mechanism have so far failed to reliably predict the coexistence of significantly more than ten alleles. We here present an eco-evolutionary model showing that evolution can result in the emergence and maintenance of more than 100 alleles under HA if the following two assumptions are fulfilled: first, pathogens are lethal in the absence of an appropriate immune defence; second, the effect of pathogens depends on host condition, with hosts in poorer condition being affected more strongly. Thus, our results show that HA can be a more potent force in explaining the extraordinary polymorphism found at MHC loci than currently recognized.
