Use of whole genome deep sequencing to define emerging minority variants in virus envelope genes in herpesvirus treated with novel antimicrobial K21.

Autor: Tweedy JG; Department of Pathogen Molecular Biology, London School Hygiene & Tropical Medicine, University of London, UK., Prusty BK; Biocenter, Chair of Microbiology, University of Wurzberg, Germany., Gompels UA; Department of Pathogen Molecular Biology, London School Hygiene & Tropical Medicine, University of London, UK. Electronic address: ursula.gompels@lshtm.ac.uk.
Jazyk: angličtina
Zdroj: Antiviral research [Antiviral Res] 2017 Oct; Vol. 146, pp. 201-204. Date of Electronic Publication: 2017 Sep 19.
DOI: 10.1016/j.antiviral.2017.09.011
Abstrakt: New antivirals are required to prevent rising antimicrobial resistance from replication inhibitors. The aim of this study was to analyse the range of emerging mutations in herpesvirus by whole genome deep sequencing. We tested human herpesvirus 6 treatment with novel antiviral K21, where evidence indicated distinct effects on virus envelope proteins. We treated BACmid cloned virus in order to analyse mechanisms and candidate targets for resistance. Illumina based next generation sequencing technology enabled analyses of mutations in 85 genes to depths of 10,000 per base detecting low prevalent minority variants (<1%). After four passages in tissue culture the untreated virus accumulated mutations in infected cells giving an emerging mixed population (45-73%) of non-synonymous SNPs in six genes including two envelope glycoproteins. Strikingly, treatment with K21 did not accumulate the passage mutations; instead a high frequency mutation was selected in envelope protein gQ2, part of the gH/gL complex essential for herpesvirus infection. This introduced a stop codon encoding a truncation mutation previously observed in increased virion production. There was reduced detection of the glycoprotein complex in infected cells. This supports a novel pathway for K21 targeting virion envelopes distinct from replication inhibition.
(Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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