Contrasting effect of new HCMV pUL54 mutations on antiviral drug susceptibility: Benefits and limits of 3D analysis.

Autor: Andouard D; Univ. Limoges, UMR, 1092, Limoges, France; INSERM, UMR, 1092, Limoges, France; CHU Limoges, Laboratoire de Bactériologie-Virologie-Hygiène, National Reference Center for Cytomegaloviruses (NRC), Limoges, France., Mazeron MC; CHU Saint Louis, Laboratoire de Bactériologie-Virologie, NRC-Associated Laboratory, Paris, France., Ligat G; Univ. Limoges, UMR, 1092, Limoges, France; INSERM, UMR, 1092, Limoges, France; CHU Limoges, Laboratoire de Bactériologie-Virologie-Hygiène, National Reference Center for Cytomegaloviruses (NRC), Limoges, France., Couvreux A; Univ. Limoges, UMR, 1092, Limoges, France; INSERM, UMR, 1092, Limoges, France; CHU Limoges, Laboratoire de Bactériologie-Virologie-Hygiène, National Reference Center for Cytomegaloviruses (NRC), Limoges, France., Pouteil-Noble C; CHU Lyon, Service de Transplantation rénale, Hôpital Edouard Herriot, Lyon, France., Cahen R; CHU Lyon, Service de Transplantation rénale, Hôpital Edouard Herriot, Lyon, France., Yasdanpanah Y; CHU Bichat, Service de Maladies infectieuses et Tropicales, Paris, France., Deering M; Univ. Limoges, UMR, 1092, Limoges, France; INSERM, UMR, 1092, Limoges, France; CHU Limoges, Laboratoire de Bactériologie-Virologie-Hygiène, National Reference Center for Cytomegaloviruses (NRC), Limoges, France., Viget N; Department of Infectious Diseases, Lille School of Medicine, Tourcoing Hospital, Tourcoing, France., Alain S; Univ. Limoges, UMR, 1092, Limoges, France; INSERM, UMR, 1092, Limoges, France; CHU Limoges, Laboratoire de Bactériologie-Virologie-Hygiène, National Reference Center for Cytomegaloviruses (NRC), Limoges, France., Hantz S; Univ. Limoges, UMR, 1092, Limoges, France; INSERM, UMR, 1092, Limoges, France; CHU Limoges, Laboratoire de Bactériologie-Virologie-Hygiène, National Reference Center for Cytomegaloviruses (NRC), Limoges, France. Electronic address: sebastien.hantz@unilim.fr.
Jazyk: angličtina
Zdroj: Antiviral research [Antiviral Res] 2016 May; Vol. 129, pp. 115-119. Date of Electronic Publication: 2016 Feb 10.
DOI: 10.1016/j.antiviral.2016.02.004
Abstrakt: Human cytomegalovirus (HCMV) resistance to antiviral drugs is a major drawback of repeated or long-duration treatment in immunocompromised patients. Resistance testing is usually performed by genotypic assays. For accurate interpretation of these assays, the role of new mutations in HCMV resistance has to be assessed. Two previously unknown UL54 single point mutations (D515Y and V787A) were characterized for phenotypic drug-resistance by marker transfer analysis using bacterial artificial chromosome (BAC) mutagenesis. Increases in 50% inhibitory concentrations of ganciclovir and foscarnet were found for both mutated recombinant strains showing that mutations D515Y and V787A induce resistance to both antivirals. Importantly, none of those impacted the viral growth kinetics. For a better understanding of their molecular resistance mechanisms, a 3D homology model was used to localize the mutated amino-acids in functional domains of UL54 and predict their impact on UL54 function and resistance. However, 3D homology model analysis has limits and phenotypic characterization using BAC-HCMV is still essential to measure the role of unknown mutations.
(Copyright © 2016 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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