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Antiviral Research (v.65, #1)

Prelim II: Editorial Board (pp. ii).

Prelim V: Instructions to Authors (pp. v-vii).

Inside Back Cover: Notes to Authors (pp. co3).

Combination of inhibitors of lymphocyte activation (hydroxyurea, trimidox, and didox) and reverse transcriptase (didanosine) suppresses development of murine retrovirus-induced lymphoproliferative disease by Christopher N. Mayhew; Ryan Sumpter; Mohammed Inayat; Michael Cibull; Jonathan D. Phillips; Howard L. Elford; Vincent S. Gallicchio (pp. 13-22).

The ribonucleotide reductase inhibitor hydroxyurea (HU) has demonstrated some benefit as a component of drug cocktails for the treatment of HIV-1 infection. However, HU is notoriously myelosuppressive and often administered only as salvage therapy to patients with late-stage disease, potentially exacerbating the bone marrow toxicity of HU. In this report we have compared the antiviral effects of HU and two novel RR inhibitors trimidox (3,4,5-trihydroxybenzamidoxime) and didox (3,4-dihydroxybenzohydroxamic acid) in combination with didanosine (2,3-didoxyinosine; ddI) in the LPBM5 MuLV retrovirus model (murine AIDS). We also evaluated the effects of these drug combinations on the hematopoietic tissues of LPBM5 MuLV-infected animals. The combination of RR inhibitors and ddI was extremely effective (DX>TX>HU) in inhibiting development of retrovirus-induced disease (splenomegaly, hypergammaglobulinemia, activated B-splenocytes and loss of splenic architecture). In addition, relative levels of proviral DNA were significantly lower in combination drug-treated animals compared to infected controls. Evaluation of femur cellularity, numbers of marrow-derived myeloid progenitor cells (CFU-GM and BFU-E) and peripheral blood indices revealed that TX and DX in combination with ddI were well-tolerated. However, treatment with HU and ddI induced moderate myelosuppression. These data demonstrate that RR inhibitors in combination with ddI provide significant protection against retroviral disease in murine AIDS. Moreover, the novel RR inhibitors TX and DX appear to be more effective and less myelosuppressive than HU when administered with ddI in this model.

Keywords: Lymphocyte activation; Reverse transcriptase; Lymphoproliferative disease

Enhancement of antiviral activity against hepatitis C virus in vitro by interferon combination therapy by Chiaki Okuse; Jo Ann Rinaudo; Kristine Farrar; Frances Wells; Brent E. Korba (pp. 23-34).

Alpha, beta, and gamma interferons (IFN-α, IFN-β, IFN-γ) have been shown to be effective inhibitors of HCV replication in human cell lines carrying HCV replicons. To help define the divergent cellular processes involved in the control of intracellular HCV replication by these agents, we have characterized the activity of monotherapies and combination therapies with the major types of human interferons against HCV replication in the HCV replicon-containing cell line, AVA5. IFN-α, IFN-β, and omega interferon (IFN-ω) were equally effective at inhibiting HCV replication, while IFN-γ was approximately 10-fold more potent. In kinetic experiments, IFN-β and IFN-γ inhibited HCV replication more rapidly, and for a more prolonged period following the removal of treatment, than IFN-α. Combination interferon therapies produced enhanced anti-HCV activity in most cases, and displayed a diverse range of interactions. Mixtures of IFN-α and IFN-β exhibited generally additive to slightly antagonistic interactions, IFN-α or IFN-β combined with IFN-ω were strongly antagonistic, while IFN-α/IFN-γ and IFN-β/IFN-γ combinations displayed the most enhanced and strongly synergistic antiviral effects. Simultaneous administration of interferons in the combination treatments was found to be superior to sequential administration. Ribavirin did not exhibit any selective anti-HCV activity in cell culture, consistent with in vivo monotherapies, and did not influence the effectiveness of IFN-α in combination treatments. A panel of human cytokines and immune response modifiers induced by interferon and ribavirin therapies in vivo did not demonstrate anti-HCV activity in HCV replicon-containing cultures. Combination therapy can be effectively modeled using HCV replicon technology yielding potentially more effective treatment regimens. HCV replicon technology has potential utility in designing combination therapies to significantly enhance the anti-HCV activity of IFN-α.

Keywords: Hepatitis C Virus; Combination antiviral therapy; Interferon; Cytokines; HCV replicon

The non-nucleoside antiviral, BAY 38-4766, protects against cytomegalovirus (CMV) disease and mortality in immunocompromised guinea pigs by Mark R. Schleiss; David I. Bernstein; Michael A. McVoy; Greg Stroup; Fernando Bravo; Blaine Creasy; Alistair McGregor; Kristin Henninger; Sabine Hallenberger (pp. 35-43).

New antiviral drugs are needed for the treatment of cytomegalovirus (CMV) infections, particularly in immunocompromised patients. These studies evaluated the in vitro and in vivo activity of the non-nucleosidic CMV inhibitor, BAY 38-4766, against guinea pig cytomegalovirus (GPCMV). Plaque reduction assays indicated that BAY 38-4766 was active against GPCMV, with an IC₅₀ of 0.5μM. Yield reduction assays demonstrated an ED₉₀ and ED₉₉ of 0.4 and 0.6μM, respectively, of BAY 38-4766 against GPCMV. Guinea pigs tolerated oral administration of 50mg/kg/day of BAY 38-4766 without evidence of biochemical or hematologic toxicity. Plasma concentrations of BAY 38-4766 were high following oral dosing, with a mean peak level at 1-h post-dose of 26.7mg/ml ( n=6; range, 17.8–35.4). Treatment with BAY 38-4766 reduced both viremia and DNAemia, as determined by a real-time PCR assay, following GPCMV infection of cyclophosphamide-immunosuppressed strain 2 guinea pigs ( p<0.05, Mann–Whitney test). BAY 38-4766 also reduced mortality following lethal GPCMV challenge in immunosuppressed Hartley guinea pigs, from 83% (20/24) in placebo-treated guinea pigs, to 17% (4/24) in BAY 38-4766-treated animals ( p<0.0001, Fisher's exact test). Mortality differences were accompanied by reduction in DNAemia in Hartley guinea pigs. Based upon its favorable safety, pharmacokinetic, and therapeutic profiles, BAY 38-4766 warrants further investigation in the GPCMV model.

Keywords: Guinea pig; Cytomegalovirus; Antiviral therapy; CMV infection; Immunocompromised animal model; Real-time PCR; BAY 38-4766; Placenta

Inhibition of SARS-CoV replication by siRNA by Chang-Jer Wu; Hui-Wen Huang; Chiu-Yi Liu; Cheng-Fong Hong; Yi-Lin Chan (pp. 45-48).

Serious outbreaks of severe acute respiratory syndrome (SARS), caused by the newly discovered coronavirus SARS-CoV, occurred between late 2002 and early 2003 and there is an urgent need for effective antiviral agents. RNA interference in animals and post-transcriptional gene silencing plants is mediated by small double-stranded RNA molecules named small interfering RNA (siRNA). Recently, siRNA-induced RNA interference(RNAi) may provide a new approach to therapy for pathogenic viruses, e.g. HIV and HCV. In this study, the silencing potential of seven synthetic siRNAs against SARS-CoV leader, TRS, 3′-UTR and Spike coding sequence have been applied to explore the possibility for prevention of SARS-CoV infection. We demonstrate that siRNAs directed against Spike sequences and the 3′-UTR can inhibit the replication of SARS-CoV in Vero-E6 cells, and holds out promise for the development of an effective antiviral agent against SARS-CoV.

Keywords: SARS-CoV; siRNA; Spike protein; Antiviral agent

Comparative efficacy of acyclovir and vidarabine on the replication of varicella-zoster virus by Naoko Miwa; Kunikazu Kurosaki; Yoshihiro Yoshida; Masahiko Kurokawa; Shigeru Saito; Kimiyasu Shiraki (pp. 49-55).

Acyclovir and less frequently, vidarabine are (or have been) used in the treatment of varicella-zoster virus (VZV) infection and are administered either intravenously (vidarabine) or orally (acyclovir, up to five times per day). The pharmacological bases of the administration interval were modeled in vitro in this study. Incubation of VZV-infected cultures with acyclovir or vidarabine for 24, 48, 72 and 96h showed similar duration-dependent anti-viral activities as assessed by a plaque-reduction assay. Treatment with vidarabine for only 8h/day for 4 days (intermittent treatment) showed anti-VZV activity equivalent to that of continuous treatment for 4 days in terms of the inhibitory dose that reduced plaque formation by 50% (IC₅₀). In contrast, intermittent treatment with acyclovir exhibited a 7.9 times higher IC₅₀ value than that of continuous treatment. The mode of inhibition of expression of most of viral protein was similar in both drugs, but the degree of inhibition was different for each protein. Thus, vidarabine with a limited period of treatment showed anti-VZV activity comparable to continuous treatment with acyclovir, indicating the longer duration of anti-viral activity of vidarabine.

Keywords: Vidarabine; Acyclovir; Varicella-zoster virus; Infection; Drug resistance

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Antiviral Research (v.65, #1)