The Diverse Roles of Heparan Sulfate in RNA Virus Infections: Insights From Enterovirus A71, Severe Acute Respiratory Syndrome Coronavirus 2, and Chikungunya Virus

Heparan sulfate (HS), a ubiquitously expressed glycosaminoglycan, functions as an attachment and/or internalization factor for diverse RNA and DNA viruses. Its broad viral attachment capacity arises from structural heterogeneity in sulfation patterns. This review examines HS interactions in enterovirus A71 (EV-A71), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and chikungunya virus (CHIKV), emphasizing shared features and virus-specific distinctions. HS mediates viral attachment in all three, and additionally promotes SARS-CoV-2 internalization when host receptor angiotensin-converting 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-A71 and SARS-CoV-2, though evidence for CHIKV remains inconclusive. In vivo, elevated HS affinity is associated with viral attenuation and diminished inflammatory responses for both EV-A71 and CHIKV; in EV-A71 specifically, increased HS affinity further correlates with reduced capsid stability and heightened sensitivity to neutralizing antibodies. HS mimetics targeting viral-HS interactions represent promising broad-spectrum antivirals, particularly those advancing in clinical trials.