title: Gene deletions in Mycobacterium bovis BCG stimulate increased CD8+ T cell responses.
abstract: Mycobacteria, the etiological agents of tuberculosis and leprosy, have coevolved with mammals for millions of years and have numerous ways of suppressing their host's immune response. It has been suggested that mycobacteria may contain genes that reduce the host's ability to elicit CD8(+) T cell responses. We screened 3,290 mutant Mycobacterium bovis bacillus Calmette Guerin (BCG) strains to identify genes that decrease major histocompatibility complex (MHC) class I presentation of mycobacterium-encoded epitope peptides. Through our analysis, we identified 16 mutant BCG strains that generated increased transgene product-specific CD8(+) T cell responses. The genes disrupted in these mutant strains had disparate predicted functions. Reconstruction of strains via targeted deletion of genes identified in the screen recapitulated the enhanced immunogenicity phenotype of the original mutant strains. When we introduced the simian immunodeficiency virus (SIV) gag gene into several of these novel BCG strains, we observed enhanced SIV Gag-specific CD8(+) T cell responses in vivo. This study demonstrates that mycobacteria carry numerous genes that act to dampen CD8(+) T cell responses and suggests that genetic modification of these genes may generate a novel group of recombinant BCG strains capable of serving as more effective and immunogenic vaccine vectors.
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Panas
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts USA.
authors.forename: Jaimie D
authors.initials: JD
authors.lastname: Sixsmith
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts USA.
authors.forename: KeriAnn
authors.initials: K
authors.lastname: White
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Korioth-Schmitz
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts USA.
authors.forename: Shana T
authors.initials: ST
authors.lastname: Shields
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Moy
authors.affiliation: Human Vaccine Institute and Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Sunhee
authors.initials: S
authors.lastname: Lee
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts USA.
authors.forename: Joern E
authors.initials: JE
authors.lastname: Schmitz
authors.affiliation: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.affiliation: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.affiliation: Human Vaccine Institute and Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts USA.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts USA geoff.gillard1@gmail.com.
authors.forename: Geoffrey O
authors.initials: GO
authors.lastname: Gillard
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017353:Gene Deletion; D007108:Immune Tolerance; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000235:genetics* / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D054301:gag Gene Products, Human Immunodeficiency Virus