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

Abstract

Herpes simplex virus (HSV) strain 1737, acyclovir-resistant and uniformly thymidine kinasedeficient (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(s)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 phenotypo. 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 antivitals may be required for effective therapy.