{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:18:29Z","timestamp":1753877909282,"version":"3.41.2"},"reference-count":95,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,3,2]],"date-time":"2020-03-02T00:00:00Z","timestamp":1583107200000},"content-version":"vor","delay-in-days":61,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004795","name":"Institut Universitaire de France","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004795","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The study of mutational landscapes of viral proteins is fundamental for the understanding of the mechanisms of cross-resistance to drugs and the design of effective therapeutic strategies based on several drugs. Antiviral therapy with nucleos(t)ide analogues targeting the hepatitis B virus (HBV) polymerase protein (Pol) can inhibit disease progression by suppression of HBV replication and makes it an important case study. In HBV, treatment may fail due to the emergence of drug-resistant mutants. Primary and compensatory mutations have been associated with lamivudine resistance, whereas more complex mutational patterns are responsible for resistance to other HBV antiviral drugs. So far, all known drug-resistance mutations are located in one of the four Pol domains, called reverse transcriptase. We demonstrate that sequence covariation identifies drug-resistance mutations in viral sequences. A new algorithmic strategy, BIS2TreeAnalyzer, is designed to apply the coevolution analysis method BIS2, successfully used in the past on small sets of conserved sequences, to large sets of evolutionary related sequences. When applied to HBV, BIS2TreeAnalyzer highlights diversified viral solutions by discovering thirty-seven positions coevolving with residues known to be associated with drug resistance and located on the four Pol domains. These results suggest a sequential mechanism of emergence for some mutational patterns. They reveal complex combinations of positions involved in HBV drug resistance and contribute with new information to the landscape of HBV evolutionary solutions. The computational approach is general and can be applied to other viral sequences when compensatory mutations are presumed.<\/jats:p>","DOI":"10.1093\/ve\/veaa006","type":"journal-article","created":{"date-parts":[[2020,1,14]],"date-time":"2020-01-14T07:12:12Z","timestamp":1578985932000},"source":"Crossref","is-referenced-by-count":4,"title":["Coevolution analysis of amino-acids reveals diversified drug-resistance solutions in viral sequences: a case study of hepatitis B virus"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0691-9654","authenticated-orcid":false,"given":"Elin","family":"Teppa","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, Univ P6, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB) - UMR 7238, 4 Place Jussieu, 75005 Paris, France"},{"name":"Sorbonne Universit\u00e9, Institut des Sciences du Calcul et des Donn\u00e9es (ISCD), 4 Place Jussieu, 75005 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Nadalin","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, Univ P6, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB) - UMR 7238, 4 Place Jussieu, 75005 Paris, France"},{"name":"Institute Curie, PSL Research University, INSERM U932, Immunity and Cancer Department, 26 rue d\u2019Ulm, 75248 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christophe","family":"Combet","sequence":"first","affiliation":[{"name":"Univ Lyon, Universit\u00e9 Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre L\u00e9on B\u00e9rard, Centre de recherche en canc\u00e9rologie de Lyon, 151 Cours Albert Thomas, 69424 Lyon, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego Javier","family":"Zea","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, Univ P6, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB) - UMR 7238, 4 Place Jussieu, 75005 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent","family":"David","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, Univ P6, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB) - UMR 7238, 4 Place Jussieu, 75005 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2098-5743","authenticated-orcid":false,"given":"Alessandra","family":"Carbone","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, Univ P6, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB) - UMR 7238, 4 Place Jussieu, 75005 Paris, France"},{"name":"Institut Universitaire de France, 1 rue Descartes, 75231 Paris, 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