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Their prime virulence determinant is the polybasic hemagglutinin (HA) cleavage site. However, required coadaptations in the HA (and other genes) remained uncertain. Here, we identified the dual motif 123R\/124I in the HA head that increases the activation pH of HA-mediated membrane fusion, essential for virus genome release into the cytoplasm. This motif is extremely predominant in H5 HPAIV and emerged already in the earliest 1997 H5N1 HPAIV. Reversion to 123S or 124T, characteristic of low-pathogenic strains, attenuated the virus in chicken and mice, accompanied by a decreased HA activation pH. This increased pH sensitivity of H5 HPAIV extends the viral tropism to cells with less-acidic endosomes, e.g., within the respiratory tract. Therefore, early HA adaptation to increased acid sensitivity promoted the emergence of H5 Goose\/Guangdong-like HPAIV strains and is required for their zoonotic potential.<\/jats:p>","DOI":"10.1128\/jvi.00778-18","type":"journal-article","created":{"date-parts":[[2018,6,12]],"date-time":"2018-06-12T06:00:25Z","timestamp":1528783225000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["A Dual Motif in the Hemagglutinin of H5N1 Goose\/Guangdong-Like Highly Pathogenic Avian Influenza Virus Strains Is Conserved from Their Early Evolution and Increases both Membrane Fusion pH and Virulence"],"prefix":"10.1128","volume":"92","author":[{"given":"Ute","family":"Wessels","sequence":"first","affiliation":[{"name":"Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, 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