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Published online ahead of print on 29 April 2009 as doi:10.1099/vir.0.011221-0
Journal of General Virology 2009;90:1937.

A more recent version of this article appeared on August 1, 2009 J Gen Virol (2009), DOI 10.1099/vir.0.011221-0
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A mutation in helicase motif IV of HSV-1 UL5 that results in reduced growth in vitro and lower virulence in a murine infection model is related to predicted helicase structure

Subhajit Biswas1,3, Ricardo Núñez Miguel1, Soumi Sukla1 and Hugh J. Field2

1 University of Cambridge;
2 Cambridge University

3 E-mail: sb507{at}cam.ac.uk

A variant was selected from a clinical isolate of HSV-1 during a single passage in the presence of a helicase-primase inhibitor (HPI) at 8 times the IC50 concentration. The variant was approx. 40-fold resistant and 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 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.

Received 20 February 2009; accepted 24 April 2009.




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