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Despite their clinical relevance, widespread prevalence, and expanding genetic diversity, no approved vaccines or antiviral therapies are available. Progress toward effective interventions requires a comprehensive understanding of HAstV molecular biology, including mechanisms of cell entry, viral replication, and immune recognition. In this review, we summarize current knowledge of HAstV epidemiology, clinical manifestations, evolution, and taxonomy, emphasizing recent advances in molecular and structural virology. We examine the HAstV replication cycle, including emerging insights into receptor usage, double-membrane vesicle biogenesis, protease-driven maturation, the capsid\u2019s membrane-lytic activity, and virion uncoating. Recent advances in determining high-resolution structures of the capsid core and spike of classical and non-classical HAstVs are highlighted, providing a framework for understanding virion assembly, maturation, and antibody neutralization. These molecular and structural insights highlight conserved and clade-specific vulnerabilities, refine current models of HAstV biology, and identify key molecular determinants that may serve as targets for antiviral development and vaccine design. We also outline critical unresolved questions that define priorities for future research.<\/jats:p>","DOI":"10.1128\/mmbr.00255-25","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:01:22Z","timestamp":1792674082000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Human astroviruses: molecular virology"],"prefix":"10.1128","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2628-3712","authenticated-orcid":false,"given":"Adam","family":"Lentz","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03s65by71","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Environmental Toxicology, University of California Santa Cruz","place":["Santa Cruz, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3699-306X","authenticated-orcid":false,"given":"Tom\u00e1s","family":"L\u00f3pez","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01tmp8f25","id-type":"ROR","asserted-by":"publisher"}],"name":"Departamento de Gen\u00e9tica del Desarrollo y Fisiolog\u00eda Molecular, Universidad Nacional Aut\u00f3noma de M\u00e9xico","place":["Cuernavaca, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5995-0663","authenticated-orcid":true,"given":"Matthew","family":"Ykema","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008zs3103","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of BioSciences, Rice University","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0149-2241","authenticated-orcid":true,"given":"Yizhi Jane","family":"Tao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008zs3103","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of BioSciences, Rice University","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4185-5673","authenticated-orcid":true,"given":"Rebecca M.","family":"DuBois","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03s65by71","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomolecular Engineering, University of California Santa Cruz","place":["Santa Cruz, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3130-4501","authenticated-orcid":true,"given":"Carlos F.","family":"Arias","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01tmp8f25","id-type":"ROR","asserted-by":"publisher"}],"name":"Departamento de Gen\u00e9tica del Desarrollo y Fisiolog\u00eda Molecular, Universidad Nacional Aut\u00f3noma de M\u00e9xico","place":["Cuernavaca, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","published-online":{"date-parts":[[2026,10,22]]},"reference":[{"key":"e_1_3_2_2_2","first-page":"609","volume-title":"Fields Virology","author":"M\u00e9ndez E","year":"2013","unstructured":"M\u00e9ndez E, Arias CF. 2013. 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