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The error-prone nature of viral RNA replication drives the high mutation rates, and the consequently high genetic diversity affects viral fitness over this transmission cycle. A few studies have been performed to investigate the intrahost genetic diversity between hosts, although their mosquito infections were performed artificially in the laboratory setting. Here, we performed whole-genome deep sequencing of DENV-1 (n = 11) and DENV-4 (n = 13) derived from clinical samples and field-caught mosquitoes from the houses of naturally infected patients, in order to analyze the intrahost genetic diversity of DENV between host types. Prominent differences in DENV intrahost diversity were observed in the viral population structure between DENV-1 and DENV-4, which appear to be associated with differing selection pressures. Interestingly, three single amino acid substitutions in the NS2A (K81R), NS3 (K107R), and NS5 (I563V) proteins in DENV-4 appear to be specifically acquired during infection in Ae. aegypti mosquitoes. Our in vitro study shows that the NS2A (K81R) mutant replicates similarly to the wild-type infectious clone-derived virus, while the NS3 (K107R), and NS5 (I563V) mutants have prolonged replication kinetics in the early phase in both Vero and C6\/36 cells. These findings suggest that DENV is subjected to selection pressure in both mosquito and human hosts. The NS3 and NS5 genes may be specific targets of diversifying selection that play essential roles in early processing, RNA replication, and infectious particle production, and they are potentially adaptive at the population level during host switching.<\/jats:p>","DOI":"10.3390\/v15040982","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T04:45:32Z","timestamp":1681706732000},"page":"982","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Intrahost Genetic Diversity of Dengue Virus in Human Hosts and Mosquito Vectors under Natural Conditions Which Impact Replicative Fitness In Vitro"],"prefix":"10.3390","volume":"15","author":[{"given":"Patcharaporn","family":"Nonyong","sequence":"first","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2406-2356","authenticated-orcid":false,"given":"Tipaya","family":"Ekalaksananan","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supranee","family":"Phanthanawiboon","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7604-3785","authenticated-orcid":false,"given":"Hans J.","family":"Overgaard","sequence":"additional","affiliation":[{"name":"Faculty of Science and Technology, Norwegian University of Life Sciences, P.O. Box 5003, 1432 \u00c5s, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6707-7876","authenticated-orcid":false,"given":"Neal","family":"Alexander","sequence":"additional","affiliation":[{"name":"MRC International Statistics and Epidemiology Group, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kesorn","family":"Thaewnongiew","sequence":"additional","affiliation":[{"name":"Department of Disease Control, Office of Disease Prevention and Control, Region 7 Khon Kaen, Ministry of Public Health, Khon Kaen 40000, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vorthon","family":"Sawaswong","sequence":"additional","affiliation":[{"name":"Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pattaraporn","family":"Nimsamer","sequence":"additional","affiliation":[{"name":"Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunchai","family":"Payungporn","sequence":"additional","affiliation":[{"name":"Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6739-0144","authenticated-orcid":false,"given":"Juthamas","family":"Phadungsombat","sequence":"additional","affiliation":[{"name":"Mahidol-Osaka Center for Infectious Diseases (MOCID), Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0477-0980","authenticated-orcid":false,"given":"Emi E.","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Mahidol-Osaka Center for Infectious Diseases (MOCID), Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand"},{"name":"Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3439-8331","authenticated-orcid":false,"given":"Tatsuo","family":"Shioda","sequence":"additional","affiliation":[{"name":"Mahidol-Osaka Center for Infectious Diseases (MOCID), Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand"},{"name":"Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2797-043X","authenticated-orcid":false,"given":"Chamsai","family":"Pientong","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1016\/S1473-3099(16)00026-8","article-title":"The global burden of dengue: An analysis from the Global Burden of Disease Study 2013","volume":"16","author":"Stanaway","year":"2016","journal-title":"Lancet Infect. 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