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2025-10-22T11:31:30Z urn:hdl:20.500.12327/2804 Evolutionary-Related High- and Low-Virulent Classical Swine Fever Virus Isolates Reveal Viral Determinants of Virulence Hinojosa, Yoandry Liniger, Matthias García-Nicolás, Obdulio Gerber, Markus Rajaratnam, Anojen Muñoz-González, Sara Coronado, Liani Frías, María Teresa Perera, Carmen Laura Ganges, Llilianne Ruggli, Nicolas Producció Animal Sanitat Animal Classical swine fever (CSF) has been eradicated from Western and Central Europe but remains endemic in parts of Central and South America, Asia, and the Caribbean. CSF virus (CSFV) has been endemic in Cuba since 1993, most likely following an escape of the highly virulent Margarita/1958 strain. In recent years, chronic and persistent infections with low-virulent CSFV have been observed. Amino acid substitutions located in immunodominant epitopes of the envelope glycoprotein E2 of the attenuated isolates were attributed to positive selection due to suboptimal vaccination and control. To obtain a complete picture of the mutations involved in attenuation, we applied forward and reverse genetics using the evolutionary-related low-virulent CSFV/Pinar del Rio (CSF1058)/2010 (PdR) and highly virulent Margarita/1958 isolates. Sequence comparison of the two viruses recovered from experimental infections in pigs revealed 40 amino acid differences. Interestingly, the amino acid substitutions clustered in E2 and the NS5A and NS5B proteins. A long poly-uridine sequence was identified previously in the 3′ untranslated region (UTR) of PdR. We constructed functional cDNA clones of the PdR and Margarita strains and generated eight recombinant viruses by introducing single or multiple gene fragments from Margarita into the PdR backbone. All chimeric viruses had comparable replication characteristics in porcine monocytederived macrophages. Recombinant PdR viruses carrying either E2 or NS5A/NS5B of Margarita, with 36 or 5 uridines in the 3′UTR, remained low virulent in 3-month-old pigs. The combination of these elements recovered the high-virulent Margarita phenotype. These results show that CSFV evolution towards attenuated variants in the field involved mutations in both structural and non-structural proteins and the UTRs, which act synergistically to determine virulence. 2025-10-22T11:31:30Z 2025-10-22T11:31:30Z 2024-01-19 info:eu-repo/semantics/article Hinojosa, Yoandry, Matthias Liniger, Obdulio García-Nicolás, Marlène Gerber, Anojen Rajaratnam, Sara Muñoz-González, Liani Coronado, et al. 2024. “Evolutionary-Related High- and Low-Virulent Classical Swine Fever Virus Isolates Reveal Viral Determinants of Virulence.” Viruses 16 (1): 147. doi: 10.3390/v16010147. 1999-4915 http://hdl.handle.net/20.500.12327/2804 https://doi.org/10.3390/v16010147 eng Viruses http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Attribution 4.0 International MDPI