title: Human cytomegalovirus (CMV) susceptibility to currently approved antiviral drugs does not impact on CMV terminase complex polymorphism.
abstract: Currently approved anti-human cytomegalovirus (CMV) drugs, all targeting the viral DNA polymerase, are associated with significant toxicities and emergence of drug resistance. In this context, CMV terminase complex constitutes a promising target for novel antiviral compounds. In this study, we describe the low natural polymorphism (interstrain identity >97.7% at both nucleotide and amino acid levels) of the terminase subunits pUL56 and pUL89, and the portal protein pUL104, among 63 CMV clinical strains, and we show that the CMV resistance profile to current DNA polymerase inhibitors has no impact on the natural polymorphism of CMV terminase complex. These results support the idea that both CMV clinical strains exhibiting either susceptibility or resistance to current CMV DNA polymerase inhibitors are comparably sensitive to novel inhibitors of CMV terminase complex, such as letermovir.
authors.affiliation: Laboratoire Universitaire de Biodiversité et d'Ecologie Microbienne, EA3882, Faculté de Médecine, Université Européenne de Bretagne, F-29609 Brest, France; Laboratoire de Virologie, CHRU de la Cavale Blanche, F-29609 Brest, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Pilorgé
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), F-75013 Paris, France; INSERM, U1135, CIMI-Paris, F-75013 Paris, France; AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière - Charles Foix, Service de Virologie, F-75013 Paris, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Burrel
authors.affiliation: AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière - Charles Foix, Service de Virologie, F-75013 Paris, France.
authors.forename: Zaïna
authors.initials: Z
authors.lastname: Aït-Arkoub
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), F-75013 Paris, France; INSERM, U1135, CIMI-Paris, F-75013 Paris, France; AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière - Charles Foix, Service de Virologie, F-75013 Paris, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Agut
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), F-75013 Paris, France; INSERM, U1135, CIMI-Paris, F-75013 Paris, France; AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière - Charles Foix, Service de Virologie, F-75013 Paris, France. Electronic address: david.boutolleau@psl.aphp.fr.
authors.forename: David
authors.initials: D
authors.lastname: Boutolleau
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000145:classification / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D003586:Cytomegalovirus Infections / Q000821:virology*; D024882:Drug Resistance, Viral; D004706:Endodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D010802:Phylogeny; D011110:Polymorphism, Genetic; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D015678:Viral Structural Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; C090238:UL56 protein, cytomegalovirus; C436448:UL89 protein, Cytomegalovirus; D014764:Viral Proteins; D015678:Viral Structural Proteins; D004706:Endodeoxyribonucleases; C030894:terminase
keywords: Human cytomegalovirus; Natural polymorphism; Resistance to DNA polymerase inhibitors; Terminase complex