Spontaneous reactivation of thymidine kinase-deficient, acyclovir-resistant type 2 herpes simplex virus: Masked heterogeneity or reversion?

Herpes simplex virus (HSV) strain 1737, acyclovir-resistant and uniformly thymidine kinase-deficient (tk(D)) by all conventional assays, clinically reactivated in an AIDS patient in the absence of antiviral drug pressure. Investigation of its neurovirulence and latency characteristics in a mouse model using a tk(D) plaque isolate (1737-14), however, yielded a neurovirulent, homogeneous, acyclovir-sensitive, tk wild type (tk(WT)) strain (1737-14ME), while trigeminal ganglia from a surviving animal yielded a heterogeneous tk(D)/tk(WT) population (1737-14/10(5)B). Heterogeneity may have arisen due to selection of a preexisting tk(WT) subpopulation or to genetic reversion. ''Ultralow'' levels of tk, undetectable by conventional means, may be sufficient for reactivation while retaining the acyclovir-resistant phenotype. A possible mechanism for spontaneous reactivation of 1737 is in vivo complementation between heterogeneous tk populations. Eradication of acyclovir-resistant, tk(D) virus does not ensure subsequent reactivations to be acyclovir-sensitive, and alternating antivirals may be required for effective therapy.