Downloaded from www.microbiologyresearch.org by IP: 54.145.26.59 On: Tue, 08 Mar 2016 20:28:58 Inactivated parapoxvirus ovis (Orf virus) has antiviral activity against hepatitis B virus and herpes simplex virus Olaf Weber, 1 3 Angela Siegling, 1 4 Astrid Friebe, 2 Andreas Limmer, 3 Tobias Schlapp, 4 Percy Knolle, 3 Andrew Mercer, 5 Heinz Schaller 3 and Hans-Dieter Volk 2 Correspondence Olaf Weber Olaf.Weber.b@bayer.com 1 BAYER AG Pharmaceutical Division, Antiinfective Research, D-42096 Wuppertal, Germany 2 Institute of Medical Immunology, Humboldt University Berlin, Medical School (Charite ´ ), Campus Mitte, D-10098 Berlin, Germany 3 Zentrum fu ¨ r Molekulare Biologie (ZMBH), Ruprecht Karls University, D-69120 Heidelberg, Germany 4 BAYER AG Animal Health R&D/Bio, Leverkusen, Germany 5 Department of Microbiology, Virus Research Unit, University of Otago, Dunedin, New Zealand Received 31 January 2003 Accepted 5 April 2003 It is known that some viruses are able to induce vigorous immune reactions. This study shows that inactivated parapoxvirus ovis (Orf virus), strain D1701 (PPVO), induces an autoregulatory cytokine response that involves the upregulation of IL-12, IL-18, IFN-c and other T helper 1-type cytokines and their subsequent downregulation, which is accompanied by induction of IL-4. An increase in IL-10 expression was also found in the livers of PPVO-treated mice. PPVO protects mice from lethal herpes simplex virus type 1 infection and guinea pigs from recurrent genital herpes disease. With dosages as low as 500 000 virus particles, PPVO is more potent than the current standard 3TC therapy in hepatitis B virus transgenic mice. No signs of inflammation or any other side effects were observed. PPVO induces IL-12, TNF-a and, together with a suboptimal concentration of Concanavalin A, IFN-c in human peripheral blood leukocytes as well. The principle of an autoregulatory cytokine induction by an inactivated virus might have advantages over existing immune therapies and it is concluded that inactivated PPVO should be investigated further for its potential use in antiviral therapy. INTRODUCTION Viruses can manipulate the immune system by bypassing or suppressing an immune reaction or by activation of the immune system (Lane et al., 1985; Mocarski, 2002; del Val et al., 1992; Mossman, 2002; Grandvaux et al., 2002). Parapoxvirus ovis (PPVO or Orf virus), a member of the family Poxviridae, causes an acute skin disease of sheep and goats worldwide and may infect humans (Haig & Mercer, 1998). The virus can infect its host repeatedly, in spite of a vigorous inflammatory host immune response, and neutralizing antibodies have not been described (Haig & Mercer, 1998; Haig & McInnes, 2002). A number of efficient immune escape mechanisms have been proposed or des- cribed for PPVO (Haig & Mercer, 1998; Haig & McInnes, 2002; McKeever et al., 1988; Haig et al., 1996, 1997; Kruse & Weber, 2001). Like other viruses, PPVO is able to stimulate the innate immune system. PPVO induces phagocytosis, NK cell activity and release of IFN-a, TNF- a, IL-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (Buettner et al., 1995; Foerster et al., 1994; Marsig & Stickl, 1988; Mayr et al., 1989). Gene products with immune-modulating functions that have been identi- fied in PPVO include virus orthologues of IL-10 (Fleming et al., 1997) and the vaccinia E3L gene encoding an interferon-resistance factor (Haig et al., 1998). Recently, proteins that bind and inhibit GM-CSF and IL-2 have been described (Dean et al., 2000). The combination of immune escape mechanisms and immune stimulatory activity is a very effective survival strategy for PPVO. Virus infections may modulate the clinical course of con- comitant infections by other pathogens. It was demonstrated 3Present address: Bayer Corporation, Pharmaceutical Division, Department of Cancer Research, 400 Morgan Lane, West Haven, CT 06516-4175, USA. 4Present address: Mixis France, Faculte ´ de Me ´ dicine Necker, 156, rue de Vaugirard, 75015 Paris, France. Published ahead of print on 30 April 2003 as DOI 10.1099/ vir.0.19138-0 0001-9138 G 2003 SGM Printed in Great Britain 1843 Journal of General Virology (2003), 84, 1843–1852 DOI 10.1099/vir.0.19138-0