Acyclovir-Resistant Herpes Simplex Virus Infection Due to Altered Dna Polymerase

Characterization of a DNA Polymerase Mutant of Herpes Simplex Virus from a Severely Immunocompromised Patient Receiving Acyclovir

“…The clinical course and details of the virus isolates are summarized in Fig. 1 and are presented in greater detail by Parker et al (1987). Briefly, a M-year-old woman with chronic myeloid leukaemia in accelerated phase underwent bone marrow transplantation in October 1985.…”

“…In fact, in isolates of HSV from normal individuals TK-deficient virus can be detected at a frequency of approximately 1/1000 (Smith et al, 1980), and it is likely that on exposure to ACV resistance occurs as a result of selection of these variants. In this paper we present data on a series of ACVresistant HSV clinical isolates from a severely immunocompromised patient in which resistance was not due to TK deficiency but rather to mutation in the DNA polymerase gene (Parker et al, 1987). Plaque-purified variants of the isolates have been characterized biochemically, and nucleotide sequence data from the polymerase gene revealed that the resistant phenotype was due to a single amino acid substitution.…”

Resistance of herpesviruses to antiviral drugs

“…The most compelling evidence indicating that a single-base change leading to an amino acid change is all that is needed for resistance to occur results from site-specific mutagenesis studies on the cloned HSV-1 polymerase expressed in yeast (37,52). As a result of the clinical use of acyclovir, selection of two distinct polymerase mutants has occurred, and the DNA polymerase gene of both mutants has been sequenced (11,39,58,60).…”

“…One DNA pol mutant contained a single-base change of glycine to serine at position 341 in region III on the polymerase (11,58), and the otherpol mutant contained a change of tyrosine to histidine at position 941 in a region designated VII (39). With the increasing recognition of polymerase mutants associated with antiviral drug use, it is likely that more mutations will be identified, and they may be identified in regions on the pol gene which have not yet been associated with resistance.…”

"The end of innocence" revisited: resistance of herpesviruses to antiviral drugs

“…The emergence of herpes simplex viruses (HSV) resistant to antiviral drugs was not a new observation, for selection for resistance has generally not been difficult in cell culture (29). Indeed, resistant HSV had also been recovered from patients (26,42,104,105), but these viruses were not associated with, nor did they cause, progressive disease in the immunocompetent patient (7). However, the emergence of drug-resistant herpesviruses in the immunosuppressed patient did result in progressive disease, as described in the articles accompanying the editorial (15,46,47), as well as elsewhere (90).…”