Cell Culture Studies on Antiviral Agents: I. Action of Cytosine Arabinoside and Some Comparisons with 5-Iodo-2-Deoxyuridine.

Mutants of herpes simplex virus type 1, resistant to phosphonoformate (PFA) and phosphonoacetate (PAA), have been selected in cell culture. The PFAresistant mutant (HSV-PFAr) and the PAA-resistant mutant (HSV-PAAr) were also resistant to PAA and PFA, respectively. This cross-resistance indicates that PFA and PAA interact at the same site. The HSV-PFAr had a decreased susceptibility to vidarabine, but no difference in sensitivity to idoxuridine (5-iodo-2'-deoxyuridine) was observed when compared to the wild type. The induced deoxyribonucleic acid polymerases isolated from cells infected with HSV-PFAr and HSV-PAAr were both cross-resistant to inhibition by PFA and PAA. No increased resistance to vidarabine triphosphate could be observed, but the susceptibility to inhibition by pyrophosphate was about two times lower. None of the mutants showed any increased temperature sensitivity Phosphonoformate (PFA) has been found to be active against herpesvirus replication in cell culture (5,16) and to have a therapeutic effect on cutaneous herpes simplex virus (HSV) infection in guinea pigs (1, 5). The deoxyribonucleic acid (DNA) polymerase induced by HSV was inhibited by PFA, indicating that this was the mechanism of inhibition in the infected cell (5). Reno et al. (16) have reported that mutants of herpesvirus of turkeys resistant to phosphonoacetate (PAA) were also resistant to PFA. From a practical point of view it is important to establish how readily resistance develops to an antiviral drug and to know to what extent a mutant resistant to one inhibitor will be susceptible to other inhibitors. This information is also of interest in understanding the mechanism of inhibition. It has been suggested earlier (6) that the development of mutants resistant to an inhibitor is a good indication of a specific antiviral activity.In this paper, the possibility to select HSV mutants resistant to PFA, the characteristics of these mutants, and their induced DNA polymerases have been investigated. Mutants resistant to PFA and the structurally related PAA (see Fig. 1

Section: Resultssupporting

confidence: 54%

Characteristics of Herpesvirus Mutants Resistant to Phosphonoformate and Phosphonoacetate

Eriksson¹,

Öberg²

1979

“…This resistance to PAA was maintained after additional passages in the absence of the antiviral agent. Drug-resistant mutant HSV populations have also been obtained with 5-iodo-2'-deoxyuridine and it has been demonstrated that such mutant populations remain stable during subsequent passages in the absence of 5-iodo-2'-deoxyuridine (1).…”

Section: Discussionmentioning

confidence: 93%

Phosphonoacetic Acid-Resistant Herpes Simplex Virus Infection in Hairless Mice

Klein

Friedman‐Kien

1975

Phosphonoacetic acid (PAA)-resistant type 1 herpes simplex virus population was isolated by repeated passage of the virus in the presence of this inhibitor. Hairless mice infected percutaneously with the inhibitor-resistant or the parental inhibitor-susceptible virus were treated intraperitoneally with PAA and 9-β- d -arabinofuranosyl-adenine by using several different dosage schedules. Whereas 9-β- d -arabinofuranosyl-adenine was effective both in the PAA-susceptible and PAA-resistant herpes simplex virus-induced skin infection, PAA suppressed only the infection induced by the parental PAA-susceptible virus.

“…Apart from our partial report of case VOL. 3,1973 on May 11, 2018 by guest http://aac.asm.org/ Downloaded from 1 (6), we are aware of only one other case in the literature (10). In this case, marked clinical improvement was also temporarily related to Ara-C therapy.…”

Section: Discussionmentioning

confidence: 95%

“…Firstly, the development of viral resistance to Ara-C in vitro has not been a problem as is the case with IUdR (3,26). Secondly, toxicities with Ara-C, given in low doses, are considerably less than conventional doses of IUdR (6).…”

Section: Discussionmentioning

confidence: 97%

Cytosine Arabinoside Therapy for Herpes Simplex Encephalitis—Clinical Experience with Six Patients

Chow

Ronald

Fiala

et al. 1973

Two neonates and four adults with herpes simplex virus (HSV) encephalitis were treated with cytosine arabinoside (Ara-C). A low dose of 40 to 160 mg per m 2 per day was given for 4 to 6 days by continuous intravenous infusion and, except in two cases, by intrathecal administration. In one patient, idoxuridine (IUdR) at the dose of 1 g every 4 h was also administered after 4 days of Ara-C therapy. Both neonates and two of four adults survived. Their clinical improvement was closely related in time to the onset of therapy with Ara-C (cases 1, 2, 3) and with IUdR (case 4). In one adult who died on the 27th day of illness of a massive pulmonary embolus, postmortem examination of the brain did not disclose viral inclusions, and viral culture was negative. In the other patient who died, however, brain culture postmortem was still positive for HSV despite 4 days of Ara-C therapy. Ara-C, in addition to IUdR, may be effective in HSV encephalitis treatment, but double-blind, controlled studies appear to be necessary with these agents.