In vitro and in vivo resistance of herpes simplex virus to 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine)

Abstract

In vitro passage of the Patton strain of herpes simplex virus type 1 (HSV-1-P) in the presence of acycloguanosine (ACG) led to the emergence of a highly drug-resistant strain (HSV-1-P-ACG-R). Over 1% of virions in 6 of 15 HSV strains tested were able to form plaques in the presence of 10 mumol of ACG on first exposure to the drug. Therefore, there exists among HSV strains a broad range of susceptibilities to ACG, and some strains contain particles which are partially resistant to ACG before ever contacting the drug. HSV-1-P-ACG-R was partially resistant to iododeoxyuridine; conversely, iododeoxyuridine-resistant virus was highly resistant to ACG. ACG-resistant virus (HSV-1-P-ACG-R) was equal to its parent strain (HSV-1-P) in susceptibility to adenine arabinoside. The HSV-1-P-ACG-R strain produced corneal lesions in rabbits which were completely refractory to topical treatment with 1% unguent ACG, but responsive to 3% ACG. Partially resistant HSV could be isolated from the eyes of rabbits infected with ACG-susceptible virus and treated topically with either 1 or 3% ACG for 6 days.