Acyclovir (9-[2-hydroxyethoxymethyl]guanine or ACV) is a nucleoside analogue with considerable potential for the treatment of herpes simplex virus (HSV) infections in man. Two virus-coded enzymes are important in the mechanism of action of this drug: thymidine kinase (TK) which initiates its activation by converting it to the monophosphate and DNA polymerase whose action is inhibited by ACV triphosphate. Changes in either gene may confer resistance, but all reported mutations in the TK gene have resulted in failure of the resistant virus to induce appreciable levels of the enzyme. Such TK- mutants arise readily in tissue culture systems where the enzyme is non-essential for virus replication, but in animals they show considerably reduced pathogenicity and neurovirulence. We now describe the isolation of a resistant mutant which induces a TK of altered substrate specificity and we show that this virus retains pathogenicity for mice with only a slight attenuation of neurovirulence.

Herpes simplex virus-specific DNA sequences have been detected by Southern hybridization analysis in both central and peripheral nervous system tissues of latently infected mice. We have detected virus-specific sequences corresponding to the junction fragment but not the genomic termini, an observation first made by Rock and Fraser (Nature [London] 302:523-525, 1983). This "endless" herpes simplex virus DNA is both qualitatively and quantitatively stable in mouse neural tissue analyzed over a 4-month period. In addition, examination of DNA extracted from human trigeminal ganglia has shown herpes simplex virus DNA to be present in an "endless" form similar to that found in the mouse model system. Further restriction enzyme analysis of latently infected mouse brainstem and human trigeminal DNA has shown that this "endless" herpes simplex virus DNA is present in all four isomeric configurations.

No abstract

No abstract

No abstract