HHV-6 and Dual Drug Therapy

Wisconsin Viral Research Group, Ltd.

Physician's Corner: Dual Drug Therapy

Dual Drug Therapy

Dual Treatment of Herpesvirus Infections with Interferons and Other Antiviral Agents

Synergistic Suppression of Cytomegalovirus Replication by Beta Interferon and Ganciclovir or Acyclovir

TITLE: Inhibition of human cytomegalovirus replication by 9-(1,3-dihydroxy-2-propoxymethyl)guanine alone and in combination with human interferons.
AUTHOR: Rasmussen L; Chen PT; Mullenax JG; Merigan TC
ABSTRACT: The inhibitory action of 9-(1,3-dihydroxy-2-propoxymethyl) guanine on the replication of human cytomegalovirus was studied. Three laboratory strains (AD-169, Towne, and Davis) and three early passage (less than 10) clinical isolates were all inhibited in yield inhibition assays. In cultures infected with AD-169, virus yields could be inhibited if the drug was added as late as 3 days after the replication cycle had begun. The effects of the drug were fully reversible during the first 4 days of the viral replication cycle. Viral infectivity and viral DNA synthesis were reduced more than viral protein synthesis. Synergistic antiviral effects were observed with beta-cysteine, and to a lesser extent, with beta-serine recombinant interferons, but only over a narrow range of dose combinations.
SOURCE: Antimicrob Agents Chemother 1984 Oct; 26(4):441-5

TITLE: Synergistic antiviral activity of acyclovir and interferon on human cytomegalovirus.
AUTHOR: Smith CA; Wigdahl B; Rapp F
ABSTRACT: The efficacy of human alpha interferon (IFN-alpha) combined with 9-(2'- hydroxyethoxymethyl) guanine (acyclovir; ACV), (E)-5-(2-bromovinyl)-2'- deoxyuridine, 9-beta-D-arabinofuranosyladenine, or 1-beta-D-arabinofuranosylcytosine on the inhibition of human cytomegalovirus(HCMV) replication in human embryonic lung cells was analyzed by plaque reduction assays. IFN-alpha combined with 9-beta-D-arabinofuranosyladenine or 1-beta-D-arabinofuranosylcytosine produced an additive antiviral activity with respect to HCMV plaque formation. IFN-alpha combined with (E)-5-(2-bromovinyl)-2'-deoxyuridine also exhibited additive antiviral activity. However, IFN-alpha combined with ACV at concentrations higher than 10 microM 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 microM) and IFN-alpha (42 IU/ml). These data suggest that combined ACV and IFN-alpha treatment may be useful against HCMV infection.
SOURCE: Antimicrob Agents Chemother 1983 Sep;24(3):325-32

Additive Suppression of Cytomegalovirus Replication by Alpha or Beta Interferon and Ganciclovir or Acyclovir

TITLE: Effects of acyclovir combined with other antiviral agents on human cytomegalovirus.
AUTHOR: Spector SA; Tyndall M; Kelley E
ABSTRACT: At present, there is no effective therapy for human cytomegalovirus (CMV) infections. Although acyclovir inhibits in vitro clinical isolates of CMV, preliminary human trials suggest that acyclovir may not be successful as a single antiviral agent in treating CMV infections. The anti CMV activity of acyclovir in combination with human fibroblast interferon (IFN-beta), phosphonoformic acid (PFA),or trifluorothymidine (TFT) was therefore evaluated. When acyclovir (20 microM) was combined with IFN-beta (25 U/ml), additive antiviral effects were observed for the four clinical CMV isolates studied and the laboratory adapted strain, AD-169. The combination of acyclovir(20 microM) with PFA (25 microM) was synergistic for all four clinical isolates studied, but additive for the AD-169 strain. Similarly, the combination of acyclovir (20 microM) and TFT (0.17 microM) was synergistic for three of four clinical isolates, and additive for one clinical strain and the AD-169 virus. These findings suggest that acyclovir combined with other antiviral agents may be useful in the treatment of CMV disease.
SOURCE: Am J Med 1982 Jul 20;73(1A):36-9

TITLE: Inhibition of human herpesviruses by combination of acyclovir and human leukocyte interferon.
AUTHOR: Levin MJ; Leary PL
ABSTRACT: Human leukocytes interferon in low concentrations (1 to 5 U/ml) enhanced the antiviral effect of acyclovir against herpes simplex virus, varicella-zoster virus, and cytomegalovirus grown in human fibroblasts. This occurred without additive inhibition of the division of human fibroblasts or proliferation of peripheral blood mononuclear cells. The combined antiviral effect was additive against clinical isolates of cytomegalovirus and was synergistic against clinical isolates of the other two viruses. The magnitude of the effect with cytomegalovirus was the same when laboratory and wild-type virus were compared. The persistence of varicella-zoster virus in the presence of acyclovir in infected human cells was also reduced by the addition of interferon.
SOURCE: Infect Immun 1981 Jun;32(3):995-9

Synergistic Suppression of Herpes Simplex Virus Replication by Interferon and Acyclovir or Ganciclovir

TITLE: Combined effects of acyclovir and human interferon-alpha on herpes simplex virus replication in cultured neural cells.
AUTHOR: Hanada N; Kido S; Kuzushima K; Goto Y; Rahman MM; Morishima T
ABSTRACT: The combined effects of Acyclovir [9-(2'-hydroxyethoxymethyl)guanine;ACV] and human interferon-alpha (IFN-alpha) on replication of the herpes simplex virus type I (HSV-1) were determined in human neural cell lines, neuroblastoma (IMR), glioblastoma (118MGC), and glioma (U251MG). HSV-1 grew well in all these cells, with final yields of more than 1 x 10(6) PFU/ml. In terms of virus-yield reduction, ACV was found to be highly effective in IMR, moderately effective in U251MG, but ineffective in 118MGC. By contrast, IFN-alpha reduced the virus yield significantly in 118MGC and in U251MG, but did not in IMR. Combined application of ACV and IFN-alpha strongly inhibited the virus replication in all three cell lines with various degrees of synergism or additive effect. These results were also confirmed by immunofluorescent examinations. The sensitivity of HSV-1 to ACV or IFN- alpha was found to be different among the three different cell types. By combining the two agents, the virus growth was strongly suppressed in all the cells. These results suggest the importance of combination therapy for severe type of herpes simplex encephalitis in clinical practice.
SOURCE: J Med Virol 1989 Sep;29(1):7-12

TITLE: Synergistic antiherpes virus activity of acyclovir and interferon in human corneal stromal cells.
AUTHOR: Taylor JL; Casey MS; O'Brien WJ
ABSTRACT: Synergistic anti-herpes simplex virus type 1 (HSV-1) activity between acyclovir (ACV) and recombinant human interferon alpha A2 (IFN) was detected in cell cultures derived from human corneas. This activity was demonstrated when cells were infected at high multipicities of infection (5 pfu/cell) in both cytopathic effect reduction and yield reduction assays as well as in plaque reduction assays at low multiplicities. The synergistic effects occurred over a 30-fold range of concentrations of IFN (6-200 IU/ml) and ACV (0.15-5 microM) at various ratios of the drugs. The augmentation of antiviral activity was greatest when cells were treated with IFN prior to infection and ACV following infection. The addition of IFN after infection, with simultaneous ACV treatment, also resulted in enhanced anti-HSV-1 activity. The combination of IFN with ACV did not increase the cytotoxicity of ACV. The synergistic antiviral activity in corneal cells may account for the previously reported enhanced efficacy of combined treatment with IFNs and nucleoside analogs for therapy of herpetic keratitis.
SOURCE: Invest Ophthalmol Vis Sci 1989 Mar;30(3):365-70

TITLE: Comparative activities of combinations of acyclovir, vidarabine or its 5'-monophosphate, and cloned human interferons against herpes simplex virus type 2 in human and mouse fibroblast cultures.
AUTHOR: Crane LR; Milne DA
ABSTRACT: Human interferon-alpha A/D (Bgl), an alpha-hybrid cloned interferon, displays activity in both human and mouse cell lines. We measured the effects of this interferon in double and triple combinations with acyclovir, vidarabine or its 5'-monophosphate against herpes simplex virus type 2 in mouse and human fibroblasts. A 75% cytopathic effect reduction assay employing a modified checkerboard technique was used. Results in human fibroblasts were compared with those obtained when recombinant human interferon-alpha 2 was substituted for the hybrid. Combinations of the hybrid interferon and nucleoside antiviral agents evoked comparable synergistic isobolograms and fractional inhibitory concentration indices in human and mouse cells versus herpes simplex virus type 2. Similar interactions were found when human interferon-alpha 2 was substituted. Uninfected cells treated with the tested combinations showed no toxicity. These data suggest that combinations of recombinant human interferon-alpha A/D (Bgl) and nucleosides in mouse models of herpes infection deserve study.
SOURCE: Antiviral Res 1985 Dec;5(6):325-33

TITLE: Potent synergistic inhibition of herpes simplex virus-2 by 9-[(1, 3-dihydroxy-2-propoxy)methyl]guanine in combination with recombinant interferons.
AUTHOR: Eppstein DA; Marsh YV
ABSTRACT: DHPG, an acyclic guanine nucleoside with the structure 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine], showed potent synergism with recombinant alpha or beta interferons and modest synergism with gamma interferon in inhibiting the replication of herpes simplex virus type 2 in vitro. The most potent direct anti-herpes viral synergism was obtained by combination of DHPG and recombinant human interferon-beta- ser17; when combined, doses of each near their separate effective dose50's resulted in almost complete elimination of production of infectious virus within a single viral replication cycle. The anti- herpes viral activity of DHPG-interferon combinations was significantly greater than that obtained with acyclovir-interferon combinations.
SOURCE: Biochem Biophys Res Commun 1984 Apr 16;120(1):66-73