title: DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV.
abstract: HIV sequence diversity and the propensity of eliciting immunodominant responses targeting variable regions of the HIV proteome are hurdles in the development of an effective AIDS vaccine. An HIV-derived conserved element (CE) p24gagplasmid DNA (pDNA) vaccine is able to redirect immunodominant responses to otherwise subdominant and often more vulnerable viral targets. By homology to the HIV immunogen, seven CE were identified in SIV p27GagAnalysis of 31 rhesus macaques vaccinated with full-length SIV gag pDNA showed inefficient induction (58% response rate) of cellular responses targeting these CE. In contrast, all 14 macaques immunized with SIV p27CE pDNA developed robust T cell responses recognizing CE. Vaccination with p27CE pDNA was also critical for the efficient induction and increased the frequency of Ag-specific T cells with cytotoxic potential (granzyme B+CD107a+) targeting subdominant CE epitopes, compared with the responses elicited by the p57gagpDNA vaccine. Following p27CE pDNA priming, two booster regimens, gag pDNA or codelivery of p27CE+gag pDNA, significantly increased the levels of CE-specific T cells. However, the CE+gag pDNA booster vaccination elicited significantly broader CE epitope recognition, and thus, a more profound alteration of the immunodominance hierarchy. Vaccination with HIV molecules showed that CE+gag pDNA booster regimen further expanded the breadth of HIV CE responses. Hence, SIV/HIV vaccine regimens comprising CE pDNA prime and CE+gag pDNA booster vaccination significantly increased cytotoxic T cell responses to subdominant highly conserved Gag epitopes and maximized response breadth.
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702.
authors.forename: Xintao
authors.identifier: 0000-0002-6552-9357
authors.initials: X
authors.lastname: Hu
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702.
authors.forename: Antonio
authors.initials: A
authors.lastname: Valentin
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702.
authors.forename: Frances
authors.initials: F
authors.lastname: Dayton
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702.
authors.forename: Viraj
authors.identifier: 0000-0002-2094-360X
authors.initials: V
authors.lastname: Kulkarni
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702.
authors.forename: Candido
authors.initials: C
authors.lastname: Alicea
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702.
authors.forename: Margherita
authors.initials: M
authors.lastname: Rosati
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702.
authors.forename: Bhabadeb
authors.initials: B
authors.lastname: Chowdhury
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Gautam
authors.affiliation: Inovio Pharmaceuticals, Plymouth Meeting, PA 19462.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Broderick
authors.affiliation: Inovio Pharmaceuticals, Plymouth Meeting, PA 19462.
authors.forename: Niranjan Y
authors.initials: NY
authors.lastname: Sardesai
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Martin
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195.|Department of Medicine, University of Washington, Seattle, WA 98195.|Department of Global Health, University of Washington, Seattle, WA 98195; and.|Department of Laboratory Medicine, University of Washington, Seattle, WA 98195.
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702; george.pavlakis@nih.gov barbara.felber@nih.gov.
authors.forename: George N
authors.initials: GN
authors.lastname: Pavlakis
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702; george.pavlakis@nih.gov barbara.felber@nih.gov.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Felber
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000818:Animals; D016207:Cytokines / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology*; D015683:Gene Products, gag / Q000276:immunology*; D006678:HIV / Q000276:immunology / Q000502:physiology; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D007115:Immunization Schedule; D007117:Immunization, Secondary / Q000379:methods; D008253:Macaca mulatta; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology / Q000502:physiology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D016207:Cytokines; D000939:Epitopes; C066594:Gag protein p27, Simian immunodeficiency virus; D015683:Gene Products, gag; D018449:SAIDS Vaccines; D019444:Vaccines, DNA