Poxviruses Bearing DNA Polymerase Mutations Show Complex Patterns of Cross-Resistance

0556926 - ÚOCHB 2023 RIV CH eng J - Článek v odborném periodiku
Andrei, G. - Fiten, P. - Krečmerová, Marcela - Opdenakker, G. - Topalis, D. - Snoeck, R.
Poxviruses Bearing DNA Polymerase Mutations Show Complex Patterns of Cross-Resistance.
Biomedicines. Roč. 10, č. 3 (2022), č. článku 580. E-ISSN 2227-9059
Grant CEP: GA MŠMT(CZ) LM2018133
Institucionální podpora: RVO:61388963
Klíčová slova: vaccinia virus * DNA polymerase * drug resistance * nucleotide analogues * cidofovir * acyclic nucleoside phosphonates * phosphonoacetic acid
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 4.7, rok: 2022
Způsob publikování: Open access
https://doi.org/10.3390/biomedicines10030580

Despite the eradication of smallpox four decades ago, poxviruses continue to be a threat to humans and animals. The arsenal of anti-poxvirus agents is very limited and understanding mechanisms of resistance to agents targeting viral DNA polymerases is fundamental for the development of antiviral therapies. We describe here the phenotypic and genotypic characterization of poxvirus DNA polymerase mutants isolated under selective pressure with different acyclic nucleoside phosphonates, including HPMPC (cidofovir), cHPMPC, HPMPA, cHPMPA, HPMPDAP, HPMPO-DAPy, and PMEO-DAPy, and the pyrophosphate analogue phosphonoacetic acid. Vaccinia virus (VACV) and cowpox virus drug-resistant viral clones emerging under drug pressure were characterized phenotypically (drug-susceptibility profile) and genotypically (DNA polymerase sequencing). Different amino acid changes in the polymerase domain and in the 3'-5' exonuclease domain were linked to drug resistance. Changes in the 3'-5' domain emerged earlier than in the polymerase domain when viruses acquired a combination of mutations. Our study highlights the importance of poxvirus DNA polymerase residues 314, 613, 684, 688, and 851, previously linked to drug resistance, and identified several novel mutations in the 3'-5' exonuclease domain (M313I, F354L, D480Y) and in the DNA polymerase domain (A632T, T831I, E856K, L924F) associated with different drug-susceptibility profiles. Furthermore, a combination of mutations resulted in complex patterns of cross-resistance. Modeling of the VACV DNA polymerase bearing the newly described mutations was performed to understand the effects of these mutations on the structure of the viral enzyme. We demonstrated the emergence of drug-resistant DNA polymerase mutations in complex patterns to be considered in case such mutations should eventually arise in the clinic.
Trvalý link: http://hdl.handle.net/11104/0331038