Differential Effects of the Type I Interferons α4, β, and ε on Antiviral Activity and Vaccine Efficacy

Abstract

The type I IFNs exert a range of activities that include antiviral, antiproliferative, and immunomodulatory effects. To study this further, we have constructed recombinant vaccinia viruses expressing HIV or hemagglutinin (HA) Ags along with murine type I IFNs, IFN-α4 (HA-VV-IFN-α4), IFN-β (HA-VV-IFN-β), or IFN-ε (HIV-VV-IFN-ε), a recently discovered member of this family. Our aims were to characterize IFN-ε functionality as a type I IFN and also to study the biological properties of these factors toward the development of safer and more effective vector-based vaccines. HIV-VV-IFN-ε and HA-VV-IFN-β grew to lower titers than did their parental controls in murine cell lines. In vivo, however, HIV-VV-IFN-ε growth was not attenuated, while IFN-β demonstrated potent local antiviral activity with no replication of HA-VV-IFN-β detected. Flow cytofluorometric analysis of B lymphocytes incubated with virally encoded IFN-ε showed up-regulation of activation markers CD69 and CD86, while RT-PCR of IFN-ε-treated cells revealed that gene expression levels of antiviral proteins were elevated, indicating the induction of an antiviral state. The use of these constructs in a poxvirus prime-boost immunization regime led to robust humoral and cellular immune responses against the encoded Ags, despite the lack of replication in the case of HA-VV-IFN-β. Thus, coexpression of these factors may be beneficial in the design of safer vector-based vaccines. Our data also indicate that while IFN-ε exhibits certain biological traits similar to other type I IFNs, it may also have a specific role in mucosal immune regulation that is quite distinct.

Pangolin genomes and the evolution of mammalian scales and immunity

“…For example, genes such as IFNE, a unique interferon exclusively expressed in skin epithelial cells and inner mucosa-protected tisssues (e.g., lung, intestines, and reproductive tissues), establish a first line of defense against pathogens in other placental mammals (Day et al 2008;Ponten et al 2008;Xi et al 2012;Fung et al 2013;Demers et al 2014;Uhlen et al 2015). Interferons (IFNs) are a cluster of highly conserved gene families that encode for cytokines expressed by host cells for communication between cells, leading to the activation of the immune system in the presence of pathogens (De Andrea et al 2002;Fensterl and Sen 2009).…”

Internal Ribosome Entry Site-Based Attenuation of a Flavivirus Candidate Vaccine and Evaluation of the Effect of Beta Interferon Coexpression on Vaccine Properties

“…Although all type I IFNs bind to a common receptor complex, binding properties and biological activities of individual IFNs (even those of closely related subtypes) may vary dramatically (see, e.g., reference 57). Thus, type I IFNs other than IFN-␤ or more distantly related IFN such as type III IFNs may provide a more optimal balance of attenuation and immunogenicity, as was reported for poxviral codelivery of several IFNs (13). Given that viruses differ in their sensitivity to different IFN types and subtypes (58,59) and that adaptive immune responses vary in their protective value against different viruses, it is likely that using the IFN coexpression strategy in vaccination will require a virus-specific optimization of IFN subtype.…”

“…6A). The MVEV.wt genome content in brain increased exponentially with time, with titers in some mice reaching almost 10 13 GEs/g of tissue (mean titer on day 4 p.i. ϭ 2.3 ϫ 10 12 GEs/g).…”

Interferon Beta and Interferon Alpha 2a Differentially Protect Head and Neck Cancer Cells from Vesicular Stomatitis Virus-Induced Oncolysis

“…Nevertheless, individual IFN subtypes are not all equally effective at inducing protection against a particular virus in a given biological system. For example, vaccinia virus (VV) vaccine vectors engineered to express IFN-␤ were significantly attenuated for replication in vitro and in vivo, while VV engineered to express IFN-␣4 replicated normally (57). Similarly, IFN-␤ protected human fibroblasts from herpes simplex virus 1 (HSV-1) and HSV-2 infection more effectively than did 5 different IFN-␣ subtypes (58), and IFN-␣6 was superior to IFN-␤ and 5 other IFN-␣ subtypes for protection against influenza virus infection in vivo (59).…”