Details

Autor(en) / Beteiligte

• Zarrouk, Karima
• Zhu, Xiaojun
• Goyette, Nathalie
• Piret, Jocelyne
• Shi, Rong
• Boivin, Guy

Titel

Differential impact of various substitutions at codon 715 in region II of HSV-1 and HCMV DNA polymerases

Ist Teil von

• Antiviral research, 2021-04, Vol.188, p.105046-105046, Article 105046

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• This study aimed at understanding the impact of different substitutions at codon 715 localized in the region II of the palm domain of herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV) DNA polymerases (pol). Here, we report a new theoretical mutation V715S that confers resistance of HSV-1 to foscarnet/acyclovir (5.6- and 9.2-fold increases EC50 values compared to wild type, respectively) and of HCMV to foscarnet/ganciclovir (2.8- and 2.9-fold increases in EC50 values compared to wild type, respectively). To further analyze the importance of this amino acid, we investigated the impact of the already known mutations V715M and V715G on the replicative capacities and drug susceptibilities of both viruses as well as on the activity and drug inhibition of the DNA pol. The V715G recombinant HSV-1 mutant was resistant to foscarnet and acyclovir (3.4- and 4.6-fold EC50 increase, respectively) whereas the V715M mutant was susceptible to foscarnet and resistant to acyclovir (3.4-fold EC50 increase). The V715G recombinant HCMV mutant did not grow and the V715M mutant was resistant to foscarnet (3.7-fold EC50 increase) and susceptible to ganciclovir. Finally, we showed by three-dimensional modeling that the differential impact of these mutations on the viral replicative capacity and drug resistance profile was related to different hydrophobic local environments for V715 in the DNA pol of the two viruses. Furthermore, we hypothesize that the DNA pol of HSV-1 is more tolerant to changes at this residue compared to that of HCMV because of a more hydrophobic environment stabilizing the region. •Substitutions at codon 715 in region II of HSV-1 and HCMV DNA polymerases differentially affects the replicative capacity.•Substitutions at codon 715 in region II of HSV-1 and HCMV DNA polymerases differentially impact the drug susceptibility.•V715 in HSV-1 and HCMV DNA polymerases is surrounded by a different local environment.•The more hydrophobic environment of V715 in HSV-1 DNA polymerase may be more tolerant to substitutions at this position.