Differential effects of the type I interferons alpha4, beta, and epsilon on antiviral activity and vaccine efficacy.
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-alpha(4) (HA-VV-IFN-alpha(4)), IFN-beta (HA-VV-IFN-beta), or IFN-epsilon (HIV-VV-IFN-epsilon), a recently discovered member of this family. Our aims were to characterize IFN-epsilon 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-epsilon and HA-VV-IFN-beta grew to lower titers than did their parental controls in murine cell lines. In vivo, however, HIV-VV-IFN-epsilon growth was not attenuated, while IFN-beta demonstrated potent local antiviral activity with no replication of HA-VV-IFN-beta detected. Flow cytofluorometric analysis of B lymphocytes incubated with virally encoded IFN-epsilon showed up-regulation of activation markers CD69 and CD86, while RT-PCR of IFN-epsilon-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-beta. Thus, coexpression of these factors may be beneficial in the design of safer vector-based vaccines. Our data also indicate that while IFN-epsilon 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.
Day
Stephanie L
SL
Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia. stephanie@anu.edu.au
Ramshaw
Ian A
IA
Ramsay
Alistair J
AJ
Ranasinghe
Charani
C
D000818:Animals; D002460:Cell Line; D004481:Ectromelia virus / Q000472:pathogenicity; D004482:Ectromelia, Infectious / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D005260:Female; D005822:Genetic Vectors; D006678:HIV / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D007117:Immunization, Secondary; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D015854:Up-Regulation; D014615:Vaccinia / Q000276:immunology; D014616:Vaccinia virus / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D014765:Viral Vaccines / Q000276:immunology*
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007370:Interferon Type I; D016898:Interferon-alpha; D014765:Viral Vaccines; D016899:Interferon-beta