Isolation and characterization of an helicase-primase inhibitor (HPI)-resistant HSV-1 mutant in tissue culture and a mouse-skin model

Biswas, Subhajit and Field, Hugh (2007) Isolation and characterization of an helicase-primase inhibitor (HPI)-resistant HSV-1 mutant in tissue culture and a mouse-skin model. Antiviral Research, 74 (3). A34-A34. ISSN 0166-3542

Full content URL: http://dx.doi.org/10.1016/j.antiviral.2007.01.026

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Item Type:Article
Item Status:Live Archive

Abstract

Nucleoside analogues currently dominate HSV therapy and drug resistance is readily selected in cell culture (>10−4) but rarely occurs in patients. Common resistant variants have defective thymidine kinase; although these mostly grow normally in tissue culture, they are often attenuated.

HPI, e.g. BAY 57-1293 are a newer class of antivirals, which have superiority over nucleoside analogues in animal infection models. BAY 57-1293-resistance could be selected by single passage in the presence of inhibitor. For example, BAYr1 is 70-fold resistant to BAY 57-1293 and occurred at a frequency of 10−6 in the well-characterized HSV-1 strain, SC16. There are previous reports that drug-resistant mutants of HSV-1 selected against BAY 57-1293 or other HPI have slower or near wild-type growth rates in vitro. However, we showed consistently that BAYr1 replicated faster in cell culture than its parent, SC16.

BAYr1 was fully pathogenic in a murine skin-infection model according to all the clinical parameters, including latency. BAYr1 was found to have two substitutions in the helicase protein (UL5: A4V and K356Q). Marker transfer revealed that K356Q alone is responsible for 70-fold resistance and faster growth in culture. Our results with BAYr1 support and extend previous reports: an HSV-1F mutant resistant to BAY 57-1293 (K356N) gave near wild-type mortality in a mouse survival test. Two mutants from HSV-1 KOS resistant to BILS 22 BS, a different HPI (K356N or G352V) grew normally in culture and were pathogenic in animal models. Our results and these two reports will be discussed in the relation to our recent surprising finding that some laboratory and clinical isolates of HSV-1 contain HPI-resistant mutants at high frequency.

Keywords:Antiviral
Subjects:B Subjects allied to Medicine > B100 Anatomy, Physiology and Pathology
Divisions:College of Science > School of Life Sciences
ID Code:12813
Deposited On:06 Jan 2014 15:51

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