Novel mutations in the thymidine kinase and DNA polymerase genes of acyclovir and foscarnet resistant herpes simplex viruses infecting an immunocompromised patient.

Abstract

Mutations in the thymidine kinase (TK) and DNA polymerase (pol) genes of herpes simplex virus (HSV) may confer resistance to antiviral drugs, particularly in the context of immunosuppression induced by infection with the human immunodeficiency virus (HIV). To characterise the HSV type 2 (HSV-2) TK and DNA pol genes in an immunocompromised patient with clinical resistance to both acyclovir and foscarnet. The TK and DNA pol genes of isolates obtained over a 2-year period from an AIDS patient with severe genital herpes infection were characterised both phenotypically and genotypically. HSV strains that were acyclovir resistant/foscarnet sensitive, acyclovir sensitive/foscarnet sensitive and acyclovir resistant/foscarnet resistant were isolated during this time. The TK gene of all the acyclovir resistant isolates contained a large 969 bp deletion which extended into a downstream untranslated region. The foscarnet resistance was associated with an S725G mutation in a conserved region (region II) of the herpesvirus DNA pol gene. Clinical and virological suppression of the infection was not always associated with subsequent reactivation with wild-type virus. Mutations of the nature we describe have not previously been reported occurring simultaneously in HSV strains isolated from patients treated with acyclovir and foscarnet.