Antiviral Activities of Cloned Human Leukocyte Interferons against Herpes Simplex Virus Type 2 Infections of Mice

Abstract

SUMMARYHuman 0t-interferons (IFN-~s) made in bacteria were examined for antiviral activity against herpes simplex virus type 2 (HSV-2) infections of mouse L-cells in vitro, and acute cervicovaginal and lethal systemic HSV-2 infections of BALB/c mice. The recombinant DNA-derived hybrid interferon IFN-ctAD(Bgl) showed pronounced antiviral activity in vitro, exceeding the activity of either of the parental subtypes IFNetA and IFN-~tD and that of the other hybrids IFN-ctAD(Pvu) and IFN-ctDA(Bgl). A combination of topical and systemic treatments with IFN-ctA and IFN-aAD(Bgl) failed to protect mice from subsequent challenge with an acute cervicovaginal infection of HSV-2. Protection from lethal systemic HSV-2 infection in mice was observed when IFN-~tAD(Bgl) and IFN-ctAD(Pvu) were administered systemically, whereas IFN-ctA failed to confer protection. These results suggest that for protection against infection with HSV-2, the routes of introduction of the virus and of the interferon influence the host response to interferon therapy.In recent years the incidence of herpesvirus genitalis has increased so dramatically that it is now regarded as one of the most widely spread of venereal diseases. Furthermore, the proposed role of herpesvirus infections in the genesis of carcinoma of the uterine cervix (Fish et al., 1982) has resulted in this virus infection becoming a leading candidate for prospective therapeutic agents.Several individual molecular species of human leukocyte interferon (IFN-ct) have been isolated and expressed in bacteria using recombinant DNA techniques (Goeddel et al., 1980;Nagata et al., 1980;Yelverton et al., 1981). Overall, the known human IFN-c~s show 52% homology at the amino acid level and each subtype differs from others in 4 to 29 amino acid positions . Because there is 84~ homology at the gene level, with common restriction endonuclease sites, it has been possible to construct genetic hybrid interferons containing portions of different parental molecules (Weck et al., 1981b;Streuli et al., 1981). Such hybrid interferons have been shown to have unique antiviral and antiproliferative activities distinct from those of the parental subtypes (Weck et al., 1981 a, b;Streuli et al., 1981 ; Lee et al., 1982a, b).We have demonstrated that human cells pretreated with various human leukocyte interferon subtypes derived from bacteria are protected against subsequent challenge with herpes simplex virus type 2 (HSV-2) . The relative degrees of protection conferred varied with the type and dose of interferon used. The subtypes IFN-ctB, IFN-ctC and IFN-~F confer least protection against HSV-2 and IFN<tA, IFN-~D and the hybrid IFN-~AD(Bgl) have the greatest effect. The present studies were designed to determine whether in vitro antiviral activity correlated with efficacy in vivo. Although natural human leukocyte interferon preparations do not show notable activity in mouse cells, the hybrid recombinant interferon IFN-ctAD(Bgl) is active both in vitro and in vivo (Weck et al., 1982).

Beta Interferon Regulation of Glucose Metabolism Is PI3K/Akt Dependent and Important for Antiviral Activity against Coxsackievirus B3

“…Our data suggest that there is a rapid and robust uptake of glucose by cells, within minutes of IFN-␤ treatment, consistent with meeting the energy demands of protein synthesis. Moreover, the nature of the biphasic response, whereby glucose uptake is initially increased, followed by a suppression, is in agreement with the paradigm of type I IFN-mediated antiproliferative effects (56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71). Specifically, in uninfected cells, the early translation of antiviral proteins is followed by a progressive shutdown of protein synthesis that would disable cell growth and, upon infection, inhibit viral protein synthesis.…”

Comparison of antiviral activities of cloned and native human interferons against herpes simplex virus types 1 and 2 and human cytomegalovirus

“…For example, interferon ax4 was only weakly effective as compared with other ao species in inhibiting both HSV and CMV. These results are in agreement with those of Fish et al (3,4), who showed that (10). It is of interest that both of the recombinant 1 interferons were more inhibitory to CMV than the ai species.…”

Type I Interferons and IRF-1 Play a Critical Role in the Control of a Gammaherpesvirus Infection

“…In all of these experiments, type I IFNs were shown to play a major role in the control of infection. Evidence for a role of type I IFNs in herpesvirus infections comes from studies on the administration IFNs (Rasmussen and Farley, 1975;Fish et al, 1983) and from work that demonstrates the importance of NK cells in clearance of infection (reviewed in Biron, 1997). Studies with EBV indicate that type I IFNs can downregulate proliferative responses to EBV in vitro (Aman and von Gabain, 1990), and evidence that the EBERs interfere with the function of IFN in vitro (Clarke et al, 1991) suggests that type I IFN activity is important in EBV infection.…”