Recurrent Acyclovir‐Resistant Herpes Simplex in an Immunocompromised Patient: Can Strain Differences Compensate for Loss of Thymidine Kinase in Pathogenesis?

Abstract

To investigate how acyclovir-resistant (ACVr) herpes simplex virus (HSV) evades drug therapy and causes disease, HSV-1 isolates from a bone marrow transplant (BMT) patient were studied. The patient developed ACVr disease after an initial BMT and, following a second BMT, reactivated ACVr HSV despite high-dose acyclovir prophylaxis. ACVr isolates from each episode contained the same point mutation in the viral thymidine kinase (tk) gene, documenting the emergence, latency, and reactivation of this mutant. The mutants were exceedingly impaired for TK activity in sensitive enzyme, plaque autoradiography, and drug-susceptibility assays. Nevertheless, these mutants and a tk deletion mutant constructed in the same genetic background reactivated from latency in mouse trigeminal ganglia, in contrast to similar mutants from laboratory strains. It is hypothesized that alleles in the clinical isolate compensate for the loss of TK in this animal model. Such genetic variability may be important for ACVr disease in humans.

Translational Compensation of a Frameshift Mutation Affecting Herpes Simplex Virus Thymidine Kinase Is Sufficient To Permit Reactivation from Latency

“…It was previously reported that virus reactivated from approximately 25% of trigeminal ganglia latently infected with the clinical isolate 615.9 and that the viruses that reactivated had a TK L phenotype (18). However, a loss of dependence on TK for reactivation has been shown for a different clinical isolate (16). The latter observation called into question the importance of the TK L phenotype in the reactivation of 615.9.…”

“…Virus 294dlTK (Fig. 1) was generated following cotransfection of p294⌬TK with infectious DNA derived from 294.1, as previously described (16). This procedure involved one round of purification under 120 M ACV, followed by three rounds of plaque purification in the absence of the drug.…”

“…It was suggested that the increased error rate during replication of long iterated sequences resulted in the emergence of a TK ϩ population that could complement the reactivation defect of the TK Ϫ virus. A third explanation for reactivation of G 7 ϩ1G mutants stems from our report describing a clinical isolate that could reactivate from latency in mouse ganglia in the absence of any TK activity (16). This observation suggests that allelic variation within the viral genome may sometimes reduce the importance of TK for pathogenesis.…”

High-Frequency Phenotypic Reversion and Pathogenicity of an Acyclovir-Resistant Herpes Simplex Virus Mutant

“…It is worth noting that the mutation suggested to confer increased heterogeneity is the same as that reported to permit the low levels of TK via ribosomal frameshifting (27). There is also evidence for another mechanism in which the virus appears to circumvent any requirement for TK in pathogenesis, possibly by a compensatory mutation elsewhere in the viral genome (15). In this study we have attempted to avoid the influence of the third mechanism by reconstituting the mutation into a laboratory strain, KOS, which has an absolute requirement for TK for reactivation from latency.…”

Treatment of an acyclovir and foscarnet-resistant herpes simplex virus infection with cidofovir in a child after an unrelated bone marrow transplant

“…Foscarnet does not require the viral thymidine kinase for its activity and is currently the only approved treatment for ACV-resistant HSV infections. 2,11 Failure of foscarnet has previously been described in HIV infections and in hematological malignancies. 2 Cross-resistance to foscarnet suggests either an alteration in the DNA polymerase or a combination of separate HSV drug-resistant populations.…”