A Targeted Mutation within the Feline Leukemia Virus (FeLV) Envelope Protein Immunosuppressive Domain To Improve a Canarypox Virus-Vectored FeLV Vaccine

Abstract

We previously delineated a highly conserved immunosuppressive (IS) domain within murine and primate retroviral envelope proteins that is critical for virus propagation in vivo. The envelope-mediated immunosuppression was assessed by the ability of the proteins, when expressed by allogeneic tumor cells normally rejected by engrafted mice, to allow these cells to escape, at least transiently, immune rejection. Using this approach, we identified key residues whose mutation (i) specifically abolishes immunosuppressive activity without affecting the "mechanical" function of the envelope protein and (ii) significantly enhances humoral and cellular immune responses elicited against the virus. The objective of this work was to study the immunosuppressive activity of the envelope protein (p15E) of feline leukemia virus (FeLV) and evaluate the effect of its abolition on the efficacy of a vaccine against FeLV. Here we demonstrate that the FeLV envelope protein is immunosuppressive in vivo and that this immunosuppressive activity can be "switched off" by targeted mutation of a specific amino acid. As a result of the introduction of the mutated envelope sequence into a previously well characterized canarypox virus-vectored vaccine (ALVAC-FeLV), the frequency of vaccine-induced FeLV-specific gamma interferon (IFN-␥)-producing cells was increased, whereas conversely, the frequency of vaccine-induced FeLV-specific interleukin-10 (IL-10)-producing cells was reduced. This shift in the IFN-␥/IL-10 response was associated with a higher efficacy of ALVAC-FeLV against FeLV infection. This study demonstrates that FeLV p15E is immunosuppressive in vivo, that the immunosuppressive domain of p15E can modulate the FeLV-specific immune response, and that the efficacy of FeLV vaccines can be enhanced by inhibiting the immunosuppressive activity of the IS domain through an appropriate mutation.

Immunosuppression in a Comparative Study of Feline Leukemia Virus Vaccines

“…As a consequence, the conclusions of this study are misleading and inconsistent with previous publications on the efficacy of canarypox-FeLV vaccine (2)(3)(4)(5).…”

“…Anti-FeLV antibodies induced by the Nobivac vaccine were still present at the time of challenge. For the canarypox-FeLV vaccine, protection is not mediated by antibodies and the FeLV-specific T-cell response plays a key role (2,5,12). Administration of large doses of MPA at the time of challenge is expected to affect the recall response to FeLV, especially the T-cell response.…”

Pseudotyped Lentiviral Vectors: One Vector, Many Guises

“…Through this approach, FeLV mutants with altered tropism were identified. [82][83][84] A more directed approach for modifying the tropism of envelopes takes advantage of specific ligand-receptor reactions. Such a ligand-based approach was demonstrated by incorporating a protein called heregulin in Mo-MLV virus envelope glycoprotein.…”

Treatment of Ebola virus infections with inhibitors of TLR4

“…In contrast, the corresponding peptide of the Reston EBOV, which is pathogenic in monkeys but not in humans, has a single mutation and did not show these effects with human cells [49]. Similarly, single mutations in the immunosuppressive domain of different retroviruses including HIV-1 also abrogated their modulating properties [47,48,50]. Furthermore, the glycoprotein of the EBOV inhibits T cell proliferation [51] as was previously demonstrated for retroviruses, their transmembrane envelope proteins and the synthetic peptide corresponding to the immunosuppressive domain (for review see [47]).…”