Mutations close to functional motif IV in HSV-1 UL5 helicase that confer resistance to HSV helicase-primase inhibitors, variously affect virus growth rate and pathogenicity

Biswas, Subhajit and Tiley, Laurence S. and Zimmermann, Holger and Birkmann, Alexander and Field, Hugh J. (2008) Mutations close to functional motif IV in HSV-1 UL5 helicase that confer resistance to HSV helicase-primase inhibitors, variously affect virus growth rate and pathogenicity. Antiviral Research, 80 (1). pp. 81-85. ISSN 0166-3542

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Abstract

Herpes simplex virus (HSV) helicase-primase (HP) is the target for a novel class of antiviral compounds, the helicase-primase inhibitors (HPIs), e.g. BAY 57-1293. Although mutations in herpesviruses conferring resistance to nucleoside analogues are commonly associated with attenuation in vivo, to date, this is not necessarily true for HPIs. HPI-resistant HSV mutants selected in tissue culture are reported to be equally pathogenic compared to parental virus in animal models. Here we demonstrate that a slow-growing HSV-1 mutant, with the BAY 57-1293-resistance mutation Gly352Arg in UL5 helicase, is clearly less virulent than its wild-type parent in a murine zosteriform infection model. This contrasts with published results obtained for a mutant containing a different HPI-resistance substitution (Gly352Val) at the same location, since this mutant was reported to be fully pathogenic. We believe our report to be the first to describe an HPI-resistant HSV-1 mutant, that is markedly less virulent in vivo and slowly growing in tissue culture compared to the parental strain. Another BAY 57-1293-resistant UL5 mutant (Lys356Gln), which showed faster growth characteristics in cell culture, however, was at least equally virulent compared to the parent strain.

Item Type:Article
Keywords:virus, growth curve, helicase, primase, BAY 57-1293, antiviral, herpes simplex
Subjects:C Biological Sciences > C540 Virology
C Biological Sciences > C520 Medical and Veterinary Microbiology
C Biological Sciences > C440 Molecular Genetics
A Medicine and Dentistry > A300 Clinical Medicine
Divisions:College of Science > School of Life Sciences
ID Code:6960
Deposited By:INVALID USER
Deposited On:26 Nov 2012 09:38
Last Modified:21 Jul 2014 08:48

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