title: Deletion of C7L and K1L genes leads to significantly decreased virulence of recombinant vaccinia virus TianTan.
abstract: The vaccinia virus TianTan (VTT) has been modified as an HIV vaccine vector in China and has shown excellent performance in immunogenicity and safety. However, its adverse effects in immunosuppressed individuals warrant the search for a safer vector in the following clinic trails. In this study, we deleted the C7L and K1L genes of VTT and constructed six recombinant vaccinia strains VTT△C7L, VTT△K1L, VTT△C7LK1L, VTKgpe△C7L, VTKgpe△K1L and VTT△C7LK1L-gag. The pathogenicity and immunogenicity of these recombinants were evaluated in mouse and rabbit models. Comparing to parental VTT, VTT△C7L and VTT△K1L showed significantly decreased replication capability in CEF, Vero, BHK-21 and HeLa cell lines. In particular, replication of VTT△C7LK1L decreased more than 10-fold in all four cell lines. The virulence of all these mutants were decreased in BALB/c mouse and rabbit models; VTT△C7LK1L once again showed the greatest attenuation, having resulted in no evident damage in mice and erythema of only 0.4 cm diameter in rabbits, compared to 1.48 cm for VTT. VTKgpe△C7L, VTKgpe△K1L and VTT△C7LK1L-gag elicited as strong cellular and humoral responses against HIV genes as did VTKgpe, while humoral immune response against the vaccinia itself was reduced by 4-8-fold. These data show that deletion of C7L and K1L genes leads to significantly decreased virulence without compromising animal host immunogenicity, and may thus be key to creating a more safe and effective HIV vaccine vector.
authors.affiliation: Division of Research on Virology and Immunology, State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention-NCAIDS, China CDC, Beijing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.forename: Shuhui
authors.initials: S
authors.lastname: Wang
authors.forename: Qicheng
authors.initials: Q
authors.lastname: Zhang
authors.forename: Meijuan
authors.initials: M
authors.lastname: Tian
authors.forename: Jue
authors.initials: J
authors.lastname: Hou
authors.forename: Rongmin
authors.initials: R
authors.lastname: Wang
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.forename: Xu
authors.initials: X
authors.lastname: Ji
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Yiming
authors.initials: Y
authors.lastname: Shao
mesh_terms: D016915:AIDS Vaccines / Q000009:adverse effects / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D005260:Female; D017353:Gene Deletion; D005814:Genes, Viral; D005822:Genetic Vectors / Q000009:adverse effects / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D006678:HIV / Q000235:genetics; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D056724:Immunity, Humoral; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011817:Rabbits; D014615:Vaccinia / Q000517:prevention & control* / Q000821:virology; D014616:Vaccinia virus / Q000235:genetics* / Q000472:pathogenicity*; D014779:Virus Replication
chemical_list: D016915:AIDS Vaccines