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Due to the considerable increase in DENV incidence and spread, symptoms such as CNS involvement have increased. Heparan sulphate (HS) was the first molecule identified as an adhesion factor for DENV in mammalian cells. Viral phenotypes with different HS interactions are associated with various clinical symptoms, including neurological alterations. Here, using <jats:italic>in silico<\/jats:italic> analyses<jats:italic>, in vitro<\/jats:italic> studies, and the <jats:italic>in vivo<\/jats:italic> mouse model, we characterized two natural circulating DENV3 genotype I (GI) lineage 1 (L1) in Brazil\u2013DENV3 MG-20 (from Minas Gerais) and DENV3 PV_BR (from Rond\u00f4nia) that present divergent neurovirulent profiles and sensitivity to sulphated molecules. We identified substitutions at the viral envelope (E) in positions 62 and 123 as likely responsible for the differences in neurovirulence. The E62K and E123Q substitutions in DENV3 MG-20 and DENV3 PV_BR, respectively, greatly influenced <jats:italic>in silico<\/jats:italic> electrostatic density and heparin docking results. <jats:italic>In vivo<\/jats:italic>, mice inoculated with DENV3 MG-20 died, but not those infected with DENV3 PV_BR. The clinical symptoms, such as paralysis of the lower limbs and meningoencephalitis, and histopathology, also differed between the inoculated groups. <jats:italic>In vitro<\/jats:italic> heparin and heparinases assays further demonstrated the biological impact of these substitutions. Other characteristics that have been previously associated with alterations in cell tropism and neurovirulence, such as changes in the size of lysis plaques and differences in cytopathic effects in glioblastoma cells, were also observed.<\/jats:p>","DOI":"10.1099\/jgv.0.001630","type":"journal-article","created":{"date-parts":[[2021,8,3]],"date-time":"2021-08-03T10:16:48Z","timestamp":1627985808000},"source":"Crossref","is-referenced-by-count":5,"title":["Dengue virus 3 genotype I shows natural changes in heparan sulphate binding sites, cell interactions, and neurovirulence in a mouse model"],"prefix":"10.1099","volume":"102","author":[{"given":"Adriana S.","family":"Andrade","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de V\u00edrus, Departamento de Microbiologia, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3324-0601","authenticated-orcid":false,"given":"Rafaela S.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica e Imunologia, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6734-0216","authenticated-orcid":false,"given":"Maria Isabel M. 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