Synergistic antiviral activity of acyclovir and interferon on human cytomegalovirus

Abstract

The efficacy of human alpha interferon (IFN-a) combined with 9-(2'-hydroxyethoxymethyl)guanine (acyclovir; ACV), (E)-5-(2-bromovinyl)-2'-deoxyuridine, 9-0-D-arabinofuranosyladenine, or 1-0-D-arabinofuranosylcytosine on the inhibition of human cytomegalovirus (HCMV) replication in human embryonic lung cells was analyzed by plaque reduction assays. IFN-a combined with 9-,B-Darabinofuranosyladenine or 1-,B-D-arabinofuranosylcytosine produced an additive antiviral activity with respect to HCMV plaque formation. IFN-a combined with (E)-5-(2-bromovinyl)-2'-deoxyuridine also exhibited additive antiviral activity. However, IFN-a combined with ACV at concentrations higher than 10 ,uM consistently yielded synergistic activity in HCMV plaque reduction assays. Kinetic analyses of HCMV replication demonstrated that approximately a 1,000-fold reduction can be attained through the synergistic interaction between ACV (200 ,uM) and IFN-a (42 IU/ml). These data suggest that combined ACV and IFNa treatment may be useful against HCMV infection.Human cytomegalovirus (HCMV) has been implicated in a wide range of clinical diseases, including intrauterine infections, perinatal infections, infections of immunosuppressed transplant and cancer patients, birth defects, and, more recently, acquired immunodeficiency disease syndrome and Kaposi sarcoma (2,14,20,24). In general, treatment of HCMV with 1-P-Darabinofuranosylcytosine (ara-C [25]), 9-P-Darabinofuranosyladenine (ara-A [19]) or human alpha interferon (IFN-a [21]) has not been successful. In addition, the newly licensed drug 9-(2'-hydroxyethoxymethyl)guanine (acyclovir; ACV) has not been effective in the treatment of HCMV pneumonia (32).Each of these compounds was initially shown to be an effective inhibitor of herpes simplex virus (HSV) and has been used to treat HSV infections (4, 5, 10, 13, 23). However, due to problems of low therapeutic indices and isolation of HSV resistant to these antiviral agents, studies have been undertaken to examine the potential of polychemotherapy in the treatment of HSV infections. Combination therapy has proven to be effective against bacterial infections and certain cancers (9, 26) and may allow decreased dosage and duration of treatment, thus reducing toxicity and the incidence of resistant virus strains.Numerous in vitro studies have examined the type of interaction (additive, synergistic, or antagonistic) of various antiherpetic compounds when used in combination. Ara-A in combination with human beta interferon (IFN-P [3]) or ACV (27) has been shown to have an additive inhibitory effect on HSV replication. Synergistic inhibitory interactions have been reported with ara-A in combination with IFN-a (16) or (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU [27]). ACV combined with IFN-a (17) or has also been shown to have a synergistic inhibitory effect on HSV replication. However, the combined interaction of ACV with BVDU has been shown to be only additive (27). ACV in combination with BVDU has also been demonstrated to have only an additive inhibitory e...

Inhibition of human cytomegalovirus replication by 9-(1,3-dihydroxy-2-propoxymethyl)guanine alone and in combination with human interferons

“…DHPG-IFN-f synergism was observed over a very limited dose range, particularly in yield inhibition assays. This is also consistent with data obtained for IFN-a-acyclovir which showed that an increase in the concentration of the drug in the presence of a constant amount of IFN changed the inhibitory effects from additive to synergistic (25). The lack of synergy between IFN-a and DHPG in inhibiting CMV is in contrast to the findings for acyclovir, a structurally related compound (10,25,27).…”

The concurrent effect of acyclovir and rosemary on glioblastoma cell culture

“…It is thought that it may be related with the presence of HCMV genome in tumor cells (6,7). One of the medications which is effective on HCMV is acyclovir (ACV) (25)(26)(27). Acyclovir is a type of nucleoside analog and well tolerated, widely used antiviral drug (28)(29)(30)(31)(32).…”

Synergistic Antiviral Effects of Acyclovir and Vidarabine on Herpes simplex Infection in Newborn Mice

“…ara-A, acyclovir, hu man immunoglobulin, interferons and their combinations have shown enhanced antiviral effects [Cho et al, 1976;Feng, 1977, 1980;Strulovitch et al, 1979;Schinazi and Nahmias, 1982;Bryson and Kronenberg, 1977]. Similar studies have been reported with varicella-zoster and human cytomegalovirus [Smith et al, 1983]. However, no one has used acyclovir-vidarabine combination therapy against HSV2 infection in newborn mice.…”