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(<jats:italic>S<\/jats:italic>)-HPMPC and its 2,6-diaminopurine counterpart, (<jats:italic>S<\/jats:italic>)-HPMPDAP, have been described to select,<jats:italic>in vitro<\/jats:italic>, for drug resistance mutations in the viral DNA polymerase (<jats:italic>E9L<\/jats:italic>) gene of vaccinia virus (VACV). Here, to extend our knowledge of drug resistance development among orthopoxviruses, we selected,<jats:italic>in vitro<\/jats:italic>, camelpox viruses (CMLV) resistant to (<jats:italic>S<\/jats:italic>)-HPMPDAP and identified a single amino acid change, T831I, and a double mutation, A314V+A684V, within E9L. The production of recombinant CMLV and VACV carrying these amino acid substitutions (T831I, A314V, or A314V+A684V) demonstrated clearly their involvement in conferring reduced sensitivity to viral DNA polymerase inhibitors, including (<jats:italic>S<\/jats:italic>)-HPMPDAP. Both CMLV and VACV harboring the A314V change showed comparable drug-susceptibility profiles to various antivirals and similar impairments in viral growth. In contrast, the single change T831I and the double change A314V+A684V in VACV were responsible for increased levels of drug resistance and for cross-resistance to viral DNA polymerase antivirals that were not observed with their CMLV counterparts. Each amino acid change accounted for an attenuated phenotype of VACV<jats:italic>in vivo<\/jats:italic>. Modeling of E9L suggested that the T\u2192I change at position 831 might abolish hydrogen bonds between E9L and the DNA backbone and have a direct impact on the incorporation of the acyclic nucleoside phosphonates. Our findings demonstrate that drug-resistance development in two related orthopoxvirus species may impact drug-susceptibility profiles and viral fitness differently.<\/jats:p>","DOI":"10.1128\/jvi.00355-12","type":"journal-article","created":{"date-parts":[[2012,4,26]],"date-time":"2012-04-26T00:16:40Z","timestamp":1335399400000},"page":"7310-7325","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":32,"title":["Mutations Conferring Resistance to Viral DNA Polymerase Inhibitors in Camelpox Virus Give Different Drug-Susceptibility Profiles in Vaccinia Virus"],"prefix":"10.1128","volume":"86","author":[{"given":"Sophie","family":"Duraffour","sequence":"first","affiliation":[{"name":"Rega Institute\u2013KU Leuven, Laboratory of Virology and Chemotherapy, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graciela","family":"Andrei","sequence":"additional","affiliation":[{"name":"Rega Institute\u2013KU Leuven, Laboratory of Virology and Chemotherapy, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitri","family":"Topalis","sequence":"additional","affiliation":[{"name":"Rega Institute\u2013KU Leuven, Laboratory of Virology and Chemotherapy, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcela","family":"Kre\u010dmerov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Marc","family":"Crance","sequence":"additional","affiliation":[{"name":"IRBA, Laboratory of Virology of the French Army, La Tronche, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Garin","sequence":"additional","affiliation":[{"name":"IRBA, Laboratory of Virology of the French Army, La Tronche, France"},{"name":"Ecole du Val-de-Gr\u00e2ce, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Snoeck","sequence":"additional","affiliation":[{"name":"Rega Institute\u2013KU Leuven, Laboratory of Virology and Chemotherapy, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1606.091187"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.2001.1343"},{"key":"e_1_3_3_4_2","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1177\/135965350701200502","article-title":"DNA polymerase mutations in drug-resistant herpes simplex virus mutants determine in vivo neurovirulence and drug-enzyme interactions","volume":"12","author":"Andrei G","year":"2007","unstructured":"AndreiG . 2007. 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