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Infection with low pathogenicity avian influenza viruses generally leads to subclinical or mild clinical disease. In contrast, highly pathogenic avian influenza viruses emerge from low pathogenic forms and can cause severe disease associated with extraordinarily high mortality rates. Here, we describe the natural history of avian influenza virus, with a focus on H5Nx and H7Nx subtypes, and the emergence of highly pathogenic forms; we review the biology of AIV; we examine cleavage of haemagglutinin by host cell enzymes with a particular emphasis on the biochemical properties of the proprotein convertases, and trypsin and trypsin\u2010like proteases; we describe mechanisms implicated in the functional evolution of the haemagglutinin cleavage site motif that leads to emergence of HPAIVs; and finally, we discuss the diversity of H5 and H7 haemagglutinin cleavage site sequence motifs. It is crucial to understand the molecular attributes that drive the emergence and evolution of HPAIVs with pandemic potential to inform risk assessments and mitigate the threat of HPAIVs to poultry and human populations.\n                  <\/jats:p>","DOI":"10.1002\/rmv.70012","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T22:44:26Z","timestamp":1735339466000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Molecular Evolution of the H5 and H7 Highly Pathogenic Avian Influenza Virus Haemagglutinin Cleavage Site Motif"],"prefix":"10.1002","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8036-110X","authenticated-orcid":false,"given":"Jasmina M.","family":"Luczo","sequence":"first","affiliation":[{"name":"Australian Animal Health Laboratory Australian Centre for Disease Preparedness Commonwealth Scientific and Industrial Research Organisation  East Geelong Australia"},{"name":"United States Department of Agriculture Exotic &amp; Emerging Avian Viral Diseases Research Southeast Poultry Research Laboratory United States National Poultry Research Center Agricultural Research Service  Athens Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Spackman","sequence":"additional","affiliation":[{"name":"United States Department of Agriculture Exotic &amp; Emerging Avian Viral Diseases Research Southeast Poultry Research Laboratory United States National Poultry Research Center Agricultural Research Service  Athens Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,27]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/mr.56.1.152\u2010179.1992"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.2307\/1589250"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1139\/m80\u2010108"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0042\u20106822(88)90260\u20107"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.79.17.11269\u201011279.2005"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102664.2010.01845.x"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf8852"},{"key":"e_1_2_12_9_1","first-page":"1","volume-title":"Manual of Diagnostic Tests and Vaccines for Terrestial Animals","author":"World Organisation for Animal Health","year":"2021"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781119371199.ch6"},{"key":"e_1_2_12_11_1","first-page":"87","article-title":"Epizoozia Tifoide Nei Gallinacei [Typhoid epizootic in fowl]","volume":"21","author":"Perroncito E.","year":"1878","journal-title":"Ann R Accad Agri Torino [Ann R Acad Agri Turin]"},{"key":"e_1_2_12_12_1","first-page":"165","volume-title":"Handbuch der Pathogenen Mikroorganismen [Handbook of Pathogenic Microorganisms]","author":"Gerlach F.","year":"1912"},{"key":"e_1_2_12_13_1","first-page":"593","article-title":"Bakteriologische studien \u00fcber die aetiologie einer epidemischen erkrankung der h\u00fchner in Tirol [Bacteriological studies on the etiology of an epidemic disease of chickens in Tyrol]","volume":"16","author":"Lode A.","year":"1901","journal-title":"Centralblatt f\u00fcr Bakteriologie, Parasitenkunde und Infektionskrankheiten [Central Journal for Bacteriology, Parasite Science and Infectious Diseases]"},{"key":"e_1_2_12_14_1","first-page":"145","article-title":"Die vogelpest. 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