title: Improving Mycobacterium bovis bacillus Calmette-Guèrin as a vaccine delivery vector for viral antigens by incorporation of glycolipid activators of NKT cells.
abstract: Recombinant Mycobacterium bovis bacillus Calmette-Guèrin (rBCG) has been explored as a vector for vaccines against HIV because of its ability to induce long lasting humoral and cell mediated immune responses. To maximize the potential for rBCG vaccines to induce effective immunity against HIV, various strategies are being employed to improve its ability to prime CD8+ T cells, which play an important role in the control of HIV infections. In this study we adopted a previously described approach of incorporating glycolipids that activate CD1d-restricted natural killer T (NKT) cells to enhance priming of CD8+ T cells by rBCG strains expressing an SIV Gag antigen (rBCG-SIV gag). We found that the incorporation of the synthetic NKT activating glycolipid α-galactosylceramide (α-GC) into rBCG-SIV gag significantly enhanced CD8+ T cell responses against an immunodominant Gag epitope, compared to responses primed by unmodified rBCG-SIV gag. The abilities of structural analogues of α-GC to enhance CD8+ T cell responses to rBCG were compared in both wild type and partially humanized mice that express human CD1d molecules in place of mouse CD1d. These studies identified an α-GC analogue known as 7DW8-5, which has previously been used successfully as an adjuvant in non-human primates, as a promising compound for enhancing immunogenicity of antigens delivered by rBCG.vectors. Our findings support the incorporation of synthetic glycolipid activators of NKT cells as a novel approach to enhance the immunogenicity of rBCG-vectored antigens for induction of CD8+ T cell responses. The glycolipid adjuvant 7DW8-5 may be a promising candidate for advancing to non-human primate and human clinical studies for the development of HIV vaccines based on rBCG vectors.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America; National Institute of Mental Health and Neuroscience, Bangalore, Karnataka, India.
authors.forename: Manjunatha M
authors.initials: MM
authors.lastname: Venkataswamy
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Tony W
authors.initials: TW
authors.lastname: Ng
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Shalu S
authors.initials: SS
authors.lastname: Kharkwal
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America; Millennium Institute on Immunology and Immunotherapy, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Leandro J
authors.initials: LJ
authors.lastname: Carreño
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Shajo
authors.initials: S
authors.lastname: Kunnath-Velayudhan
authors.affiliation: Department of Chemistry and Biochemistry, Queens College of City University of New York, Flushing, New York, United States of America.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Biochemistry, Queens College of City University of New York, Flushing, New York, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Jervis
authors.affiliation: School of Chemistry, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Liam R
authors.initials: LR
authors.lastname: Cox
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Xiangshu
authors.initials: X
authors.lastname: Wen
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Weiming
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America.
authors.forename: Moriya
authors.initials: M
authors.lastname: Tsuji
authors.affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America.
authors.forename: Xiangming
authors.initials: X
authors.lastname: Li
authors.affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America.
authors.forename: David D
authors.initials: DD
authors.lastname: Ho
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Chan
authors.affiliation: Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Sunhee
authors.initials: S
authors.lastname: Lee
authors.affiliation: Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Frothingham
authors.affiliation: Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Panas
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Geoffrey O
authors.initials: GO
authors.lastname: Gillard
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jaimie D
authors.initials: JD
authors.lastname: Sixsmith
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Birgit
authors.initials: B
authors.lastname: Korioth-Schmitz
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Joern E
authors.initials: JE
authors.lastname: Schmitz
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America; Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Larsen
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America; Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D001500:BCG Vaccine / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D017635:Clonal Anergy / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000276:immunology; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D006017:Glycolipids / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009163:Mycobacterium bovis / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D001500:BCG Vaccine; D005699:Galactosylceramides; D015683:Gene Products, gag; D006017:Glycolipids; C493154:alpha-galactosylceramide