Abstract: Herein is described a system to combat poxvirus infection wherein antagonists are developed that bind the soluble cytokine receptor but have no significant biological activity in the host, effectively blocking the virus-mediated suppressor of interferon function, thereby permitting the host's own cytokines to stimulate an antiviral response. Alternatively, interferon molecules can be developed that retain biological activity on their native receptors but fail to bind the viral cytokine binding protein, thereby circumventing this virus immune modulation mechanism.