Activity of AMP against experimental herpes simplex virus type 1 infections in mice

Abstract

Administration of AMP soon after inoculation of mice with herpes simplex virus type 1 inhibited development of virus-induced lesions and appeared to prevent establishment of virus latency. These effects were dependent on both the AMP dose and the time of AMP administration. Regression of herpes simplex virus type 1-induced lesions was also accelerated significantly by AMP treatment in a timeand dose-dependent manner.The capacity of AMP to prevent both primary and recurrent herpes simplex virus type 1 (HSV-1) infections resulting from inoculation of mouse ear pinnae has been previously reported (1). Here we report the results of therapeutic trials carried out in the same animal model system. These investigations were prompted by several reports indicating possible antiviral activities inherent in adenosine or AMP (5, 10-12), as well as by a growing list of reported pharmacological and physiological effects of adenosine and AMP (2-4, 6, 9).The mouse ear pinnae model of Hill et al. (7,8) A multiple-dose treatment regimen (four doses over a 24-h period) was used to determine the minimum dose required to completely inhibit the formation of primary lesions. AMP (Sigma Chemical Co., St. Louis, Mo.) was dissolved in phosphate-buffered saline (pH 7.4) just before use and administered intraperitoneally. Nine groups of mice received AMP at 1, 6, 12, and 24 h after inoculation with HSV-1. The individual dose required to reduce the incidence of primary ear lesions by at least 50% was 2.0 mg/kg; the total dose was 8.0 mg/kg (Table 1). The minimum 100% inhibitory dose was 10 mg/kg, or a total of 40 mg/kg over 24 h.

Components of the Nucleotide Salvage Pathway Increase Frog Virus 3 (FV3) Replication

“…We evaluated this in a FV3-permissive epithelial cell line [35,36], designated epithelioma papulosum cyprini, in an attempt to understand the role of purine salvage in FV3 infections. Contrary to other DNA viruses [13][14][15][17][18][19][20], we found that components of the purine salvage pathway, with the exception of SAH, increased FV3 replication.…”

“…Alternatively, small molecules are known to produce biphasic dose responses. As such, purines may result in stimulation of viral replication at low doses (as observed in this study), but result in inhibition at higher doses [ 13 , 14 , 15 , 17 , 18 , 19 , 20 ].…”

“…Previous reports outlining the potent antiviral capacity of purines emphasized high micromolar to millimolar concentrations [ 13 , 14 , 16 , 17 , 18 , 20 ]. These concentration ranges may be useful for establishing the antiviral capacity of purines, but may not be physiologically relevant.…”

“…In the Herpesviridae family, Epstein–Barr virus (EBV) DNA polymerase is inhibited by GMP [ 18 ]. Similarly, herpes simplex virus (HSV) is inhibited by purine salvage molecules both in vitro [ 19 ] and in vivo [ 20 ]. In vitro, 2 mM of GMP, IMP, or AMP reduces HSV DNA polymerase activity by 47.9%, 49.7%, and 66.6%, respectively [ 19 ].…”

“…In vitro, 2 mM of GMP, IMP, or AMP reduces HSV DNA polymerase activity by 47.9%, 49.7%, and 66.6%, respectively [ 19 ]. In vivo, application of AMP (EC 50 = 2.0 mg/kg) prevents the establishment of HSV latency and reduces virus-associated lesion formation [ 20 ].…”