Inactivated Orf Virus Shows Antifibrotic Activity and Inhibits Human Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) Replication in Preclinical Models

Abstract

Inactivated orf virus (iORFV), strain D1701, is a potent immune modulator in various animal species. We recently demonstrated that iORFV induces strong antiviral activity in animal models of acute and chronic viral infections. In addition, we found D1701-mediated antifibrotic effects in different rat models of liver fibrosis. In the present study, we compare iORFV derived from two different strains of ORFV, D1701 and NZ2, respectively, with respect to their antifibrotic potential as well as their potential to induce an antiviral response controlling infections with the hepatotropic pathogens hepatitis C virus (HCV) and hepatitis B virus (HBV). Both strains of ORFV showed anti-viral activity against HCV in vitro and against HBV in a transgenic mouse model without signs of necro-inflammation in vivo. Our experiments suggest that the absence of liver damage is potentially mediated by iORFV-induced downregulation of antigen cross-presentation in liver sinus endothelial cells. Furthermore, both strains showed significant anti-fibrotic activity in rat models of liver fibrosis. iORFV strain NZ2 appeared more potent compared to strain D1701 with respect to both its antiviral and antifibrotic activity on the basis of dosages estimated by titration of active virus. These results show a potential therapeutic approach against two important human liver pathogens HBV and HCV that independently addresses concomitant liver fibrosis. Further studies are required to characterize the details of the mechanisms involved in this novel therapeutic principle.

Targeting Innate and Adaptive Immune Responses to Cure Chronic HBV Infection

“…82 AIC649, an inactivated Parapoxvirus ovis particle, activates complement and TLRdependent and -independent signaling in myeloid cells to promote a T-helper 1 cell-mediated response. 83 In woodchucks, AIC649 reduced levels of HBsAg 79 . The agent displayed good safety data in a phase 1 trial of patients with chronic HBV infection.…”

Orf Virus: A New Class of Immunotherapy Drugs

“…The inactivated ORFV agents with a low dose (only 500,000 virus particles) are more effective in transgenic mice than the standard 3TC for HBV infection [66]; thus, it can be used as the candidate antiviral agent for the treatment of human HBV. Inactivated ORFV has anti-HCV activity in vitro and transgenic mice model [67]. In addition, ORFV can prevent the recurrence of fatal herpes simplex virus (HSV) and recurrence of genital herpes in Guinea [68].…”

Orf virus: A promising new therapeutic agent

“…This preparation may be used as a candidate antiviral agent for the treatment of human HBV. Inactivated ORFV D1701 and NZ2 strains have antiviral activity in HCV in vitro and transgenic mice models . In addition, inactivated ORFV agents protect mice from infection of lethal HSV‐1 and guinea pigs from HSV‐2 .…”

“…Inactivated ORFV D1701 and NZ2 strains have antiviral activity in HCV in vitro and transgenic mice models. 77 In addition, inactivated ORFV agents protect mice from infection of lethal HSV-1 and guinea pigs from HSV-2. 75,76 Pretreatment with inactivated ORFV confers resistance to infection by equine herpesvirus type 1.…”