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

Biswas, Subhajit and Nunez Miguel, Ricardo and Sukla, Soumi and Field, Hugh J. (2009) 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. Journal of General Virology, 90 (8). pp. 1937-1942. ISSN 0022-1317

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Official URL: http://vir.sgmjournals.org/content/90/8/1937.long

Abstract

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 IC(50). 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.

Item Type:Article
Keywords:BAY 57-1293, virus, herpes simplex, helicase, primase, resistance, mouse infection model, mutation, bmjaccents
Subjects:C Biological Sciences > C540 Virology
A Medicine and Dentistry > A100 Pre-clinical Medicine
C Biological Sciences > C520 Medical and Veterinary Microbiology
Divisions:College of Science > School of Life Sciences
ID Code:6958
Deposited By: Subhajit Biswas
Deposited On:25 Nov 2012 21:43
Last Modified:31 Dec 2013 14:05

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