title: 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-γ)-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-γ/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.
authors.affiliation: Unité des Rétrovirus Endogènes et Eléments Rétroïdes des Eucaryotes Supérieurs, UMR 8122 CNRS, Institut Gustave Roussy, Villejuif, and Université Paris-Sud, Orsay, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Schlecht-Louf
authors.forename: Marianne
authors.initials: M
authors.lastname: Mangeney
authors.forename: Hanane
authors.initials: H
authors.lastname: El-Garch
authors.forename: Valérie
authors.initials: V
authors.lastname: Lacombe
authors.forename: Hervé
authors.initials: H
authors.lastname: Poulet
authors.forename: Thierry
authors.initials: T
authors.lastname: Heidmann
mesh_terms: D000818:Animals; D028121:Canarypox virus / Q000235:genetics* / Q000378:metabolism; D002415:Cats; D005260:Female; D015686:Gene Products, env / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology; D007372:Interferons / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D005256:Leukemia Virus, Feline / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D016582:Leukemia, Feline / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D015682:Retroviridae Proteins, Oncogenic / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics* / Q000276:immunology
chemical_list: D015686:Gene Products, env; D007166:Immunosuppressive Agents; D015682:Retroviridae Proteins, Oncogenic; D014765:Viral Vaccines; C045569:feline leukemia virus vaccine; D016753:Interleukin-10; D007372:Interferons