Phosphonoacetic Acid-Resistant Herpes Simplex Virus Infection in Hairless Mice

Klein, Richard J.T.; Friedman‐Kien, Alvin E.

doi:10.1128/aac.7.3.289

Cited by 51 publications

(39 citation statements)

References 11 publications

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“…DISCUSSION The selection of PFA' HSV mutants can be achieved in cell cultures and is an indication of the specificity of the inhibitor (6). The ease of selecting resistant mutants (Tables 1 and 2) was similar for PFA and PAA and corresponds to earlier reports for PAA (3,7,11) and idoxuridine (2). Resistance development seems, however, to be much easier in cell culture than in animals, qs reported for PAA (3) and idoxuridine (9), or found clinically with idoxuridine (8).…”

Section: Resultssupporting

confidence: 55%

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Characteristics of Herpesvirus Mutants Resistant to Phosphonoformate and Phosphonoacetate

Eriksson¹,

Öberg²

1979

Antimicrob Agents Chemother

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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

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Section: Resultssupporting

confidence: 55%

“…The mechanism for this is unclear. It has been reported that PAA-resistant HSV infections in mice can be treated with vidarabine as effectively as the HSV wild type (11). The animal models might not be so precise as to determine minor changes in drug resistance.…”

Section: Resultsmentioning

confidence: 99%

Characteristics of Herpesvirus Mutants Resistant to Phosphonoformate and Phosphonoacetate

Eriksson¹,

Öberg²

1979

Antimicrob Agents Chemother

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“…Amino Acid Residues phonoformate (PFA) where it is relatively easy to select resistant mutants (Klein and Friedman-Klein, 1975;Hay and SubakSharpe, 1976;Honess and Watson, 1977;Eriksson and Oberg, 1979;Derse et al, 1982). One possible explanation is that PAA and PFA exert additional effects resulting in an increased mutation rate.…”

Section: Discussionmentioning

confidence: 99%

Related functional domains in virus DNA polymerases.

Larder¹,

Kemp²,

Darby³

1987

The EMBO Journal

232

160

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Analysis of the lesions in several drug-resistant DNA polymerase mutants of herpes simplex virus along with comparative analysis of the published polymerase sequences of other human herpesviruses has shown that most lesions (five out of six) are substitutions at amino acid residues conserved in all four polymerases. Furthermore, the majority of lesions are in regions of the polypeptide where there are marked clusterings of conserved residues. On the basis of these data we have identified several domains within the polypeptide which we believe may have important functional roles in the action of the enzyme. The apparent restriction in the potential sites of lesions conferring drug resistance may explain the difficulty in selecting such mutants using acyclovir (ACV) in culture and their failure to emerge so far during ACV therapy. Extension of the comparative analysis to the polymerases of adenovirus type 2, vaccinia virus and phage q29 suggests that these enzymes also possess domains homologous to those most conserved in the herpes polymerases (regions I-HI) and that these domains have a similar linear spatial distribution on the polypeptides. The results are discussed in relation to the known function of the DNA polymerases.

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“…Treatment with PAA (400 mg/kg) by the same route resulted in 46.7% survivors, with an MST of about 16 days, whereas 13.3% of the salinetreated animals survived, and the MST was 10.5 days. The ara-A and PAA concentrations used for subcutaneous treatment were previously shown to be effective in HSV-infected hamsters (32) and mice (18,31), respectively.…”

Section: Resultsmentioning

confidence: 99%

Chemotherapy of Genital Herpes Simplex Virus Type 2 Infections of Female Hamsters

Renis

1977

Antimicrob Agents Chemother

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The antiviral activity of 1-,3-n-arabinofuranosylcytosine (ara-C, cytarabine, Cytosar), 5-iodo-2'-deoxyuridine (IdUrd), 9-,8-D-arabinofuranosyladenine (ara-A), and disodium phosphonoacetate (PAA) have been compared in herpes simplex virus type 2 (HSV-2)-infected primary rabbit kidney cells and in female hamsters with genital HSV-2 infection. In vitro, ara-C and IdUrd were more active than ara-A, and PAA was least active. In female hamsters with genital HSV-2 infection, intravaginal treatment with PAA or ara-A was more effective than either ara-C or IdUrd. PAA was more active than ara-A when treatment was initiated early (1 h) after infection. The activity of PAA was greatly reduced if initiation of treatment was delayed for 24 h. Both PAA and ara-A reduced the virus titers of the vagina and protected hamsters from death when the drugs were given by either the intravaginal or subcutaneous route, with intravaginal treatment being more effective.Genital herpesvirus infections, primarily caused by herpes simplex virus type 2 (HSV-2), are transmitted by venereal contact (9, 26). The infection can be painful and recurrent. If lesions are present late during the gestation period, the neonate is at high risk, resulting in disease with high morbidity and mortality (25). Furthermore, HSV-2 has been implicated in the etiology of cervical carcinoma (2,4,23).At the present time, there is no effective treatment for genital HSV infections. However, several agents with antiherpes activity in other systems have been studied in herpes genitalis. Topical application of certain heterocyclic dyes, followed by exposure to light, has been proposed as a method for treating this disease (5). However, in subsequent studies with proflavine (34), or in a double-blind study with neutral red (24), it was not possible to demonstrate efficacy.We have recently described the experimental genital infection of female hamsters with HSV-2 (30). In the studies described herein, several drugs with reported antiherpes activity have been compared in vitro and in female hamsters with genital HSV-2 infection. MATERIALS AND METHODSVirus. Stocks of HSV-2 (strain 35D) were supplied by L. T. Chien, University of Tennessee. The virus had a titer of 7.5 x 105 to 1.0 x 0l plaque-forming units per 0.5 ml on primary rabbit kidney monolayers.In vitro antiviral activity. Contiguous monolayers of primary rabbit kidney cells were infected by incubating 0.5 ml of stock virus with drained monolayers (60-mm plastic petri dishes, Falcon) for 60 min at 370C. The monolayers were washed and refed with 4.5 ml of Eagle medium containing 3% fetal bovine serum. The drugs were prepared in Hanks solution, and 0.5 ml of the appropriate dilution was added to each plate, resulting in the concentrations indicated. The cultures were harvested to -70°C when approximately 50 to 75% of the cells in the control cultures showed evidence of cytopathology. The virus titers of the frozen-thawed cultures were determined by the plaque method on rabbit kidney monolayers.Genital infection of femal...

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Phosphonoacetic Acid-Resistant Herpes Simplex Virus Infection in Hairless Mice

Cited by 51 publications

References 11 publications

Characteristics of Herpesvirus Mutants Resistant to Phosphonoformate and Phosphonoacetate

Characteristics of Herpesvirus Mutants Resistant to Phosphonoformate and Phosphonoacetate

Related functional domains in virus DNA polymerases.

Chemotherapy of Genital Herpes Simplex Virus Type 2 Infections of Female Hamsters

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