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Its broad viral attachment capacity arises from structural heterogeneity in sulfation patterns. This review examines HS interactions in enterovirus A71 (EV\u2010A71), severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102), and chikungunya virus (CHIKV), emphasizing shared features and virus\u2010specific distinctions. HS mediates viral attachment in all three, and additionally promotes SARS\u2010CoV\u20102 internalization when host receptor angiotensin\u2010converting enzyme 2 is absent. Positively charged residues on the virion dictate HS affinity. High HS affinity enhances in vitro infectivity and plaque size in EV\u2010A71 and SARS\u2010CoV\u20102, though evidence for CHIKV remains inconclusive. In vivo, elevated HS affinity is associated with viral attenuation and diminished inflammatory responses for both EV\u2010A71 and CHIKV; in EV\u2010A71 specifically, increased HS affinity further correlates with reduced capsid stability and heightened sensitivity to neutralizing antibodies. HS mimetics targeting viral\u2010HS interactions represent promising broad\u2010spectrum antivirals, particularly those advancing in clinical trials.<\/jats:p>","DOI":"10.1002\/jmv.70888","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T11:28:04Z","timestamp":1774956484000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Diverse Roles of Heparan Sulfate in RNA Virus Infections: Insights From Enterovirus A71, Severe Acute Respiratory Syndrome Coronavirus 2, and Chikungunya Virus"],"prefix":"10.1002","volume":"98","author":[{"given":"Chun Hao","family":"Theo","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology Faculty of Medicine, Universiti Malaya Kuala Lumpur Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I\u2010Ching","family":"Sam","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology Faculty of Medicine, Universiti Malaya Kuala Lumpur Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoke Fun","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology Faculty of Medicine, Universiti Malaya Kuala Lumpur Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2012.08529.x"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2004.11.020"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36450-y"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom5032003"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a004952"},{"key":"e_1_2_15_7_1","volume-title":"Biochemistry, Glycosaminoglycans","author":"Casale 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