HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplementary Material All Versions of this Article: vir.0.011221-0v1 90/8/1937    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Biswas, S. Articles by Field, H. J. PubMed PubMed Citation Articles by Biswas, S. Articles by Field, H. J. Agricola Articles by Biswas, S. Articles by Field, H. J.

A mutation in helicase motif IV of herpes simplex virus type 1 UL5 that results in reduced growth in vitro and lower virulence in a murine infection model is related to the predicted helicase structure

Subhajit Biswas^1,

Ricardo Núñez Miguel^2,

¹ Department of Veterinary Medicine, University of Cambridge, Cambridge, UK
² Department of Biochemistry, University of Cambridge, Cambridge, UK

Correspondence
Subhajit Biswas
sb507{at}cam.ac.uk

A variant was selected from a clinical isolate of herpes simplex virus type 1 (HSV-1) during a single passage in the presence of a helicase–primase inhibitor (HPI) at eight times the IC₅₀. The variant was approximately 40-fold resistant to the HPI BAY 57-1293 and it showed significantly reduced growth in tissue culture with a concomitant reduction in virulence in a murine infection model. The variant contained a single mutation (Asn342Lys) in the UL5 predicted functional helicase motif IV. The Asn342Lys mutation was transferred to a laboratory strain, PDK cl-1, and the recombinant acquired the expected resistance and reduced growth characteristics. Comparative modelling and docking studies predicted the Asn342 position to be physically distant from the HPI interaction pocket formed by UL5 and UL52 (primase). We suggest that this mutation results in steric/allosteric modification of the HPI-binding pocket, conferring an indirect resistance to the HPI. Slower growth and moderately reduced virulence suggest that this mutation might also interfere with the helicase–primase activity.

These authors contributed equally to this work.

The atomic coordinates of the predicted HSV-1 UL5–BAY 57-1293 complex are available with the online version of this paper.