Chronic hepatitis B virus (HBV) infection is a major cause of liver disease. Only interferon-alpha and the nucleosidic inhibitors of the viral polymerase, 3TC and adefovir, are approved for therapy. However, these therapies are limited by the side effects of interferon and the substantial resistance of the virus to nucleosidic inhibitors. Potent new antiviral compounds suitable for monotherapy or combination therapy are highly desired. We describe non-nucleosidic inhibitors of HBV nucleocapsid maturation that possess in vitro and in vivo antiviral activity. These inhibitors have potential for future therapeutic regimens to combat chronic HBV infection.

The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.

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While these studies also suggest that the molecular mechanism of BAY 38-4766 is distinct from that of benzimidazole ribonucleosides, they also offer an explanation for the excellent specificity and tolerability of BAY 38-4766, since mammalian DNA does not undergo comparable maturation steps.

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Inactivated parapoxvirus ovis (Orf virus;Parapoxvirus ovis (Orf virus; PPVO) is a member of the poxvirus family and causes pustular skin lesions in sheep, goats, and humans (20). The family of poxviruses consists of large DNA viruses with strong immunogenic properties. To evade the host immune defense, poxviruses utilize a variety of immunomodulatory cellular proteins, which enable them to replicate in spite of an active immune response (1,16,17,28). Such proteins have been described for PPVO; these include a viral interleukin 10 (IL-10) homologue (11, 12), a granulocyte-macrophage colony-stimulating factor, an IL-2-inhibiting protein (8), and the product of a gene with homology to the vaccinia virus E3L gene, which counteracts interferon-induced cell resistance (18,19,21,30).The immunostimulating and modulating capacities made PPVO an interesting candidate for new antiviral strategies (36). The immunomodulatory properties of the virus could be used by means of a noninfectious preparation of inactivated PPVO to influence the clinical course of other viral infections. Thus, inactivated PPVO showed strong effects in several animal models for acute and chronic virus infections. It was effective in a guinea pig model for genital herpes disease and in a transgenic mouse model for human hepatitis B virus (HBV). In HBVtransgenic mice, PPVO led to a reduction in virus replication that was not associated with the destruction of liver cells. Furthermore, PPVO was able to reduce lethality in mice infected with herpes simplex virus. This effect also was not accompanied by a tissue-damaging inflammatory response or other side effects (36).Investigations of the cytokine expression profiles of animals treated with PPVO implicate gamma interferon (IFN-␥) as a key mediator of the PPVO-mediated activity against HBV and herpes simplex virus. Thus, the application of PPVO first led to the release of Th1-inducing or effector cytokines, such as IL-12, IL-18, and IFN-␥. The neutralization of IFN-␥ by antibodies could abolish antiviral effects in vivo. The induction of type 1 cytokines was followed by the secretion of anti-inflammatory cytokines, such as IL-4 (36). These findings indicate the induction of a limited immune response and offer an explanation for the good tolerability of the preparation in animals. The immunomodulatory properties of PPVO might be responsible for the observed antiviral effects and might contribute to the absence of systemic side effects and the absence of tissue injury that are observed after the direct administration of Th1-inducing or effector cytokines.The aim of this study was to investigate whether the effects of PPVO can be determined under controlled conditions in human immune cells. In the work presented, we evaluated the cytokine secretion of peripheral blood cells, especially IFN-␥, which has been proved in animal models to be an important factor in transducing antiviral effects. In addition, we evaluated the mechanisms that mediate the effects of PPVO.

Viruses can manipulate the immune response against them by various strategies to influence immune cells, i.e. by over-activation leading to functional inactivation, bypassing antigen presentation or even suppression of effector functions. Little is known, however, about how these features of immune regulation and modulation could be used for therapeutic purposes. Reasons for this include the complexity of immune regulatory mechanisms under certain disease conditions and the risks that infections with viruses pose to human beings. The orf virus (ORFV), a member of the Parapoxvirus genus of the poxvirus family, is known as a common pathogen in sheep and goats worldwide. The inactivated ORFV, however, has been used as a preventative as well as therapeutic immunomodulator in veterinary medicine in different species. Here, we review the key results obtained in pre-clinical studies or clinical studies in veterinary medicine to characterise the therapeutic potential of inactivated ORFV. Inactivated ORFV has strong effects on cytokine secretion in mice and human immune cells, leading to an auto-regulated loop of initial up-regulation of inflammatory and Th1-related cytokines, followed by Th2-related cytokines that attenuate immunopathology. The therapeutic potential of inactivated ORFV has been recognised in several difficult-to-treat disease areas, such as chronic viral diseases, liver fibrosis or various forms of cancer. Further research will be required in order to evaluate the full beneficial potential of inactivated ORFV for therapeutic immunomodulation.

Inhibition of constitutive and induced IKKbeta-activity through treatment with KINK-1 might increase tumor susceptibility to chemotherapy.