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J Med Virol. 2010 May;82(6):1000-6. doi: 10.1002/jmv.21773.

Neurovirulence and latency of drug-resistant clinical herpes simplex viruses in animal models.

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Research Center in Infectious Diseases, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, Université Laval, Quebec, Canada.


Herpes simplex virus (HSV) resistance to acyclovir or foscarnet results from mutations in viral thymidine kinase (TK) and/or DNA polymerase (pol) genes. Replication kinetics and virulence of TK and/or DNA pol clinical mutants were assessed using models of mouse encephalitis and cotton rat genital infection. Replication capacities in Vero cells of a DNA pol altered strain (L850I) and a TK/DNA pol mutant (C467deletion/A912V) were significantly lower than those of unrelated wild-type (WT) strains, while a double DNA pol mutant (S724N/P920S) demonstrated replication kinetics similar to the WT. The replication of a TK-deficient mutant (G439.5addition) was impaired (low m.o.i.) or unaltered (high m.o.i.) compared to that of a WT virus depending on the viral inoculum. Compared to a survival rate of 6% for mice infected intranasally with WT HSV-1 or -2 viruses, G439.5add, C467deletion/A912V and L850I strains were associated with survival rates of 100% (P < 0.05) whereas mice infected with the S724N/P920S mutant had a survival rate of 33% (P = 0.08). Brain viral titers were higher in mice infected with WT HSV-1 or -2 strains and the double DNA pol mutant. All strains except the DNA pol mutant L850I were able to establish latency in the dorsal root ganglia of cotton rats. A good correlation was generally found between replication kinetics of DNA pol mutants and their neurovirulence potential in mice whereas such correlation was not straightforward for TK mutants.

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