Interference of retroviral envelope with vaccine-induced CD8+ T cell responses is relieved by co-administration of cytokine-encoding vectors

Abstract

BackgroundRetroviral envelope (Env) proteins are known to exhibit immunosuppressive properties, which become apparent not only in retroviral infections, but also in gene-based immunizations using retroviral immunogens, where envelope interferes with the induction of CD8+ T cell responses towards another, simultaneously or subsequently delivered, immunogen.ResultsIn the Friend retrovirus mouse model, immunization with a plasmid encoding the Friend murine leukemia virus (F-MuLV) Leader-Gag protein resulted in induction of a strong GagL85–93-specific CD8+ T cell response, while the response was completely abrogated by co-immunization with an F-MuLV Env-encoding plasmid. In order to overcome this interference of retroviral envelope, we employed plasmids encoding the cytokines interleukin (IL) 1β, IL2, IL12, IL15, IL21, IL28A or granulocyte–macrophage colony-stimulating factor (GM-CSF) as genetic adjuvants. Co-application of plasmids encoding IL2, IL12, IL21, IL28A and especially GM-CSF rescued the induction of GagL85–93-specific CD8+ T cells in mice vaccinated with FV Leader-Gag and Env. Mice that were immunized with plasmids encoding Leader-Gag and Env and the cytokines IL1β, IL12, IL15, IL28A or GM-CSF, but not Leader-Gag and Env without any cytokine, showed significantly reduced viral loads upon a high-dose Friend virus challenge infection.ConclusionsOur data demonstrate the potency of cytokine-encoding vectors as adjuvants and immune modulators in composite vaccines for anti-retroviral immunization.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-017-0352-7) contains supplementary material, which is available to authorized users.

Immunization with a murine cytomegalovirus based vector encoding retrovirus envelope confers strong protection from Friend retrovirus challenge infection

“…However, we have shown that the GagL 85-93 epitope is rather weak and can be sub-dominant to vector-derived epitopes [45], which might result in impaired GagL 85-93 -specific CD8 + T cell responses in the MCMV background. We have also shown before that Env suppresses CD8 + T cell responses to simultaneously or subsequently administered immunogens [40, 46]; interestingly, we did not observe a suppressive effect of Env on MCMV-specific CD8 + T cell responses, so it would be intriguing to see if CD8 + T cell responses that are suppressed in DNA or adenovirus-based immunization are also unaffected by Env in the MCMV background.…”

Immunodominance of Adenovirus-Derived CD8 + T Cell Epitopes Interferes with the Induction of Transgene-Specific Immunity in Adenovirus-Based Immunization

“…As DBP 418 -426 did not have a dominance effect over GagL 85-93 and the dominance of hexon 486 -494 was lost in the C57BL/6 H-2D b/b background, we enquired next whether C57BL/6 mice would actually show responsiveness toward an Addelivered native leader-Gag. While we had performed immunization experiments in C57BL/6 mice in the past, in those experiments we had employed a mixture of the leader-Gag vector with an envelope-encoding vector (11), which we later showed to interfere with CD8 ϩ T cell induction (11,26). We immunized C57BL/6 mice once with Ad5.Leader-Gag, or with Ad5.Leader-Gag C1K as a positive control, and analyzed the GagL 85-93 -specific CD8 ϩ T cell response 2 weeks later by MHC I tetramer staining.…”

Innate signalling molecules as genetic adjuvants do not alter the efficacy of a DNA-based influenza A vaccine

“…Interestingly, Liu and colleagues also tested genetic adjuvants, specifically DNA-encoded Flt3L and MIP-1α, and found that either electroporation or inclusion of genetic adjuvants can both increase immunogenicity of the DNA vaccine separately, but if electroporation was applied after the injection of the adjuvants, an additive effect was barely detectable [61]. However, this might not rule out that adjuvants addressing other pathways might possess better immunostimulatory potentials in DNA electroporation [62,63] or that the adjuvants might have greater impact in immunizations with immunosuppressive antigens [64].…”