HSV-1 and HSV-2 may develop resistance to antiviral drugs under
conditions of immunosuppression induced by infections (eg HIV)
and drug therapy following organ or bone marrow transplantation.
We are conducting a study of the mechanisms by which HSV develops
virological resistance to acyclovir in a group of patients exhibiting
clinical resistance to this drug. The most common site for resistance
(in nearly 90% of isolates) is the HSV thymidine kinase (tk) gene,
the product of which is integral to the activation of acyclovir
by phosphorylation.
Insertions or deletions in homopolymer stretches of Gs and Cs
leading to translational frameshifts and a truncated tk are the
most common resistance mechanisms. However, we have also identified
several stop codons and amino acid substitutions in other locations
of the tk that are likely to confer resistance.
The HSV DNA polymerase (pol) gene is a less common site for resistance
generating mutations (approximately 12% of isolates). Most pol
mutations detected occur in conserved regions important in enzyme
function. These results have been obtained using phenotyping and
sequencing of tk and pol genes. We are currently using mutagenesis
to confirm the role of identified individual mutations in acyclovir
resistance.
