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

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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.

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