title: Interleukin-1- and type I interferon-dependent enhanced immunogenicity of an NYVAC-HIV-1 Env-Gag-Pol-Nef vaccine vector with dual deletions of type I and type II interferon-binding proteins.
abstract: NYVAC, a highly attenuated, replication-restricted poxvirus, is a safe and immunogenic vaccine vector. Deletion of immune evasion genes from the poxvirus genome is an attractive strategy for improving the immunogenic properties of poxviruses. Using systems biology approaches, we describe herein the enhanced immunological profile of NYVAC vectors expressing the HIV-1 clade C env, gag, pol, and nef genes (NYVAC-C) with single or double deletions of genes encoding type I (ΔB19R) or type II (ΔB8R) interferon (IFN)-binding proteins. Transcriptomic analyses of human monocytes infected with NYVAC-C, NYVAC-C with the B19R deletion (NYVAC-C-ΔB19R), or NYVAC-C with B8R and B19R deletions (NYVAC-C-ΔB8RB19R) revealed a concerted upregulation of innate immune pathways (IFN-stimulated genes [ISGs]) of increasing magnitude with NYVAC-C-ΔB19R and NYVAC-C-ΔB8RB19R than with NYVAC-C. Deletion of B8R and B19R resulted in an enhanced activation of IRF3, IRF7, and STAT1 and the robust production of type I IFNs and of ISGs, whose expression was inhibited by anti-type I IFN antibodies. Interestingly, NYVAC-C-ΔB8RB19R induced the production of much higher levels of proinflammatory cytokines (tumor necrosis factor [TNF], interleukin-6 [IL-6], and IL-8) than NYVAC-C or NYVAC-C-ΔB19R as well as a strong inflammasome response (caspase-1 and IL-1β) in infected monocytes. Top network analyses showed that this broad response mediated by the deletion of B8R and B19R was organized around two upregulated gene expression nodes (TNF and IRF7). Consistent with these findings, monocytes infected with NYVAC-C-ΔB8RB19R induced a stronger type I IFN-dependent and IL-1-dependent allogeneic CD4(+) T cell response than monocytes infected with NYVAC-C or NYVAC-C-ΔB19R. Dual deletion of type I and type II IFN immune evasion genes in NYVAC markedly enhanced its immunogenic properties via its induction of the increased expression of type I IFNs and IL-1β and make it an attractive candidate HIV vaccine vector.
  
  
  OBJECTIVE
  NYVAC is a replication-deficient poxvirus developed as a vaccine vector against HIV. NYVAC expresses several genes known to impair the host immune defenses by interfering with innate immune receptors, cytokines, or interferons. Given the crucial role played by interferons against viruses, we postulated that targeting the type I and type II decoy receptors used by poxvirus to subvert the host innate immune response would be an attractive approach to improve the immunogenicity of NYVAC vectors. Using systems biology approaches, we report that deletion of type I and type II IFN immune evasion genes in NYVAC poxvirus resulted in the robust expression of type I IFNs and interferon-stimulated genes (ISGs), a strong activation of the inflammasome, and upregulated expression of IL-1β and proinflammatory cytokines. Dual deletion of type I and type II IFN immune evasion genes in NYVAC poxvirus improves its immunogenic profile and makes it an attractive candidate HIV vaccine vector.
authors.affiliation: Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois, and University of Lausanne, Lausanne, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Delaloye
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, Florida, USA.
authors.forename: Abdelali
authors.initials: A
authors.lastname: Filali-Mouhim
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, Florida, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cameron
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, Florida, USA.
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
authors.affiliation: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, and University of Lausanne, Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Harari
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, Florida, USA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Goulet
authors.affiliation: Centro Nacional de Biotecnología, CSIC, Madrid, Spain.
authors.forename: Carmen E
authors.initials: CE
authors.lastname: Gomez
authors.affiliation: Centro Nacional de Biotecnología, CSIC, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Perdiguero
authors.affiliation: Centro Nacional de Biotecnología, CSIC, Madrid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Esteban
authors.affiliation: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, and University of Lausanne, Lausanne, Switzerland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pantaleo
authors.affiliation: Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois, and University of Lausanne, Lausanne, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Roger
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, Florida, USA.
authors.forename: Rafick-Pierre
authors.initials: RP
authors.lastname: Sékaly
authors.affiliation: Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois, and University of Lausanne, Lausanne, Switzerland Thierry.Calandra@chuv.ch.
authors.forename: Thierry
authors.initials: T
authors.lastname: Calandra
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005822:Genetic Vectors; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D007375:Interleukin-1 / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D017384:Sequence Deletion
chemical_list: D016915:AIDS Vaccines; D007370:Interferon Type I; D007375:Interleukin-1; C572770:NYVAC-C vaccine