Susceptibility of Herpesviruses to Three Nucleoside Analogues and Their Combinations and Enhancement of the Antiviral Effect at Acid pH

Abstract

The susceptibilities of herpes viruses to three nucleoside analogues were studied with a standardized cell-culture assay. Cytosine arabinoside (ara-C) was the most active drug; MICs were: 0.25–0.75 µg/ml for herpes simplex type 1,0.37–2.0 µg/ml for herpes simplex type 2, and 0.37–4.0 µg/ml for varicella-zoster. Adenine arabinoside (ara-A) was 20-fold less active against herpes simplex and varicella-zoster. Ara-A demonstrated an additive effect with ara-C and with 5-iodo-2′-deoxyuridine (IUDR) against herpes simplex type 1; ara-C and IUDR were antagonistic. The MIC of ara-C for 80% plaque-reduction of cytomegalovirus was 2.0–4.0 µg/ml; none of the drugs inhibited cytomegalovirus by 100%. The MICs of all three nucleoside analogues against herpes simplex virus were considerably higher when assayed at pH 8.0 rather than at pH 7.0. Herpes simplex type 2 was significantly more resistant to IUDR than herpes simplex type 1 only when tested in a strongly buffered alkaline medium. The usefulness of these in vitro antiviral assays, however, has to be demonstrated by further laboratory and clinical studies.