2. Academic Validation
  3. First clinical description of letermovir resistance mutation in cytomegalovirus UL51 gene and potential impact on the terminase complex structure

First clinical description of letermovir resistance mutation in cytomegalovirus UL51 gene and potential impact on the terminase complex structure

  • Antiviral Res. 2022 Aug;204:105361. doi: 10.1016/j.antiviral.2022.105361.
Clotilde Muller 1,  Valentin Tilloy 2,  Emilie Frobert 3,  Linda Feghoul 4,  Isabelle Garrigue 5,  Quentin Lepiller 6,  Audrey Mirand 7,  Egor Sidorov 8,  Sébastien Hantz 9,  Sophie Alain 10
Affiliations

Affiliations

  • 1 Univ. Limoges, INSERM, CHU Limoges, RESINFIT, U1092, F-87000, Limoges, France. Electronic address: clotilde.muller@unilim.fr.
  • 2 CHU Limoges, Laboratoire de Bactériologie-Virologie-Hygiène, National Reference Center for Herpesviruses (NRCHV), F-87000, Limoges, France; CHU Limoges, UF9481 Bioinformatique, F-87000, Limoges, France.
  • 3 CHU Lyon, UCL, Virology Department, Lyon, France.
  • 4 CHU Saint Louis, AP-HP, Virology Department, Paris, France.
  • 5 CHU Pellegrin, Virology Department, Bordeaux, France.
  • 6 CHU Besançon, Virology Department, Besançon, France.
  • 7 CHU Clermont-Ferrand, Virology Department, Clermont-Ferrand, France.
  • 8 CHU Limoges, Laboratoire de Bactériologie-Virologie-Hygiène, National Reference Center for Herpesviruses (NRCHV), F-87000, Limoges, France.
  • 9 Univ. Limoges, INSERM, CHU Limoges, RESINFIT, U1092, F-87000, Limoges, France; CHU Limoges, Laboratoire de Bactériologie-Virologie-Hygiène, National Reference Center for Herpesviruses (NRCHV), F-87000, Limoges, France.
  • 10 Univ. Limoges, INSERM, CHU Limoges, RESINFIT, U1092, F-87000, Limoges, France; CHU Limoges, Laboratoire de Bactériologie-Virologie-Hygiène, National Reference Center for Herpesviruses (NRCHV), F-87000, Limoges, France. Electronic address: sophie.alain@unilim.fr.
PMID: 35690130 DOI: 10.1016/j.antiviral.2022.105361
Abstract

Background: Letermovir (LMV) is a human cytomegalovirus (HCMV) terminase inhibitor indicated as prophylaxis for HCMV-positive stem-cell recipients. Its mechanism of action involves at least the viral terminase proteins pUL56, pUL89 and pUL51. Despite its efficiency, resistance mutations were characterized in vitro and in vivo, largely focused on pUL56. To date, mutations in pUL51 in clinical resistance remain to be demonstrated.

Methods: The pUL51 natural polymorphism was described by Sequencing 54 LMV-naive strains and was compared to UL51 HCMV genes from 16 patients non-responding to LMV therapy (prophylaxis or curative). Recombinant viruses were built by «en-passant» mutagenesis to measure the impact of the new mutations on Antiviral activity and viral growth. Structure prediction was performed by homology modeling. The pUL51 final-model was analyzed and aligned with the atomic coordinates of the monomeric HSV-1 terminase complex (PDB:6M5R).

Results: Among the 16 strains from treated-patients with LMV, 4 never described substitutions in pUL51 (D12E, 17del, A95V, V113L) were highlighted. These substitutions had no impact on viral fitness. Only UL51-A95V conferred 13.8-fold increased LMV resistance level by itself (IC50 = 29.246 ± 0.788).

Conclusion: As an isolated mutation in pUL51 in a clinical isolate can lead to LMV resistance, genotyping for resistance should involve Sequencing of the pUL51, pUL56 and pUL89 genes. With terminase modelling, we make the hypothesis that LMV could bind to domains were UL56-L257I and UL51-A95V mutations were localized.

Keywords

Cytomegalovirus; Herpes simplex; Letermovir; Resistance; Terminase; UL51.

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