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 (tkD) 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 tkD plaque isolate (1737-14), however, yielded a neurovirulent, homogeneous, acyclovir-sensitive, tk wild type (tkWT) strain (1737-14ME), while trigeminal ganglia from a surviving animal yielded a heterogeneous tkD/tkWT population (1737-14/10(5)B). Heterogeneity may have arisen due to selection of a preexisting tkWT 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, tkD virus does not ensure subsequent reactivations to be acyclovir-sensitive, and alternating antivirals may be required for effective therapy.
Sasadeusz
J J
JJ
Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, Canada.
Sacks
S L
SL
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications; D000212:Acyclovir / Q000494:pharmacology*; D000818:Animals; D004352:Drug Resistance, Microbial; D005260:Female; D018258:Herpesvirus 2, Human / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D016296:Mutagenesis; D011233:Precipitin Tests; D013937:Thymidine Kinase / Q000172:deficiency*; D010948:Viral Plaque Assay; D014775:Virus Activation; D017735:Virus Latency
D013937:Thymidine Kinase; D000212:Acyclovir