title: A human immune data-informed vaccine concept elicits strong and broad T-cell specificities associated with HIV-1 control in mice and macaques.
abstract: BACKGROUND
  None of the HIV T-cell vaccine candidates that have reached advanced clinical testing have been able to induce protective T cell immunity. A major reason for these failures may have been suboptimal T cell immunogen designs.
  
  
  METHODS
  To overcome this problem, we used a novel immunogen design approach that is based on functional T cell response data from more than 1,000 HIV-1 clade B and C infected individuals and which aims to direct the T cell response to the most vulnerable sites of HIV-1.
  
  
  RESULTS
  Our approach identified 16 regions in Gag, Pol, Vif and Nef that were relatively conserved and predominantly targeted by individuals with reduced viral loads. These regions formed the basis of the HIVACAT T-cell Immunogen (HTI) sequence which is 529 amino acids in length, includes more than 50 optimally defined CD4(+) and CD8(+) T-cell epitopes restricted by a wide range of HLA class I and II molecules and covers viral sites where mutations led to a dramatic reduction in viral replicative fitness. In both, C57BL/6 mice and Indian rhesus macaques immunized with an HTI-expressing DNA plasmid (DNA.HTI) induced broad and balanced T-cell responses to several segments within Gag, Pol, and Vif. DNA.HTI induced robust CD4(+) and CD8(+) T cell responses that were increased by a booster vaccination using modified virus Ankara (MVA.HTI), expanding the DNA.HTI induced response to up to 3.2% IFN-γ T-cells in macaques. HTI-specific T cells showed a central and effector memory phenotype with a significant fraction of the IFN-γ(+) CD8(+) T cells being Granzyme B(+) and able to degranulate (CD107a(+)).
  
  
  CONCLUSIONS
  These data demonstrate the immunogenicity of a novel HIV-1 T cell vaccine concept that induced broadly balanced responses to vulnerable sites of HIV-1 while avoiding the induction of responses to potential decoy targets that may divert effective T-cell responses towards variable and less protective viral determinants.
authors: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. bmothe@irsicaixa.es.|'Lluita contra la Sida' Foundation, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain. bmothe@irsicaixa.es.|Universitat de Vic-Universitat Central de Catalunya (UVic-UCC), Vic, Spain. bmothe@irsicaixa.es.
authors: Beatriz
authors: B
authors: Mothe
authors: Human Retrovirus Pathogenesis Section, National Cancer Institute-Frederick, Frederick, MD, USA. xintao.hu@nih.gov.
authors: Xintao
authors: X
authors: Hu
authors: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. ALlano@irsicaixa.es.
authors: Anuska
authors: A
authors: Llano
authors: Human Retrovirus Section, National Cancer Institute-Frederick, Frederick, MD, USA. margherita.rosati@nih.gov.
authors: Margherita
authors: M
authors: Rosati
authors: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. aolvera@irsicaixa.es.
authors: Alex
authors: A
authors: Olvera
authors: Human Retrovirus Pathogenesis Section, National Cancer Institute-Frederick, Frederick, MD, USA. kviraj@gmail.com.
authors: Viraj
authors: V
authors: Kulkarni
authors: Human Retrovirus Section, National Cancer Institute-Frederick, Frederick, MD, USA. antonio.valentin@nih.gov.
authors: Antonio
authors: A
authors: Valentin
authors: Human Retrovirus Pathogenesis Section, National Cancer Institute-Frederick, Frederick, MD, USA. candido.alicea@nih.gov.
authors: Candido
authors: C
authors: Alicea
authors: Human Retrovirus Pathogenesis Section, National Cancer Institute-Frederick, Frederick, MD, USA. guy.pilkington@nih.gov.
authors: Guy R
authors: GR
authors: Pilkington
authors: Inovio Pharmaceuticals Inc, Blue Bell, PA, USA. nsardesai@inovio.com.
authors: Niranjan Y
authors: NY
authors: Sardesai
authors: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. mrocafort@irsicaixa.es.
authors: Muntsa
authors: M
authors: Rocafort
authors: HIV Unit, Hospital de la Vall d'Hebrón, Barcelona, Spain. mcrespo@vhebron.net.
authors: Manel
authors: M
authors: Crespo
authors: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. jcarrillo@irsicaixa.es.
authors: Jorge
authors: J
authors: Carrillo
authors: Centres Penitenciaris BCN, Barcelona, Spain. amarco@aspb.cat.
authors: Andrés
authors: A
authors: Marco
authors: University of Washington, Seattle, WA, USA. jmullins@u.washington.edu.
authors: James I
authors: JI
authors: Mullins
authors: Nuffield Department of Medicine, University of Oxford, The John Radcliffe Hospital, Oxford, UK. lucy.dorrell@ndm.ox.ac.uk.
authors: Lucy
authors: L
authors: Dorrell
authors: The Jenner Institute, University of Oxford, Oxford, UK. tomas.hanke@ndm.ox.ac.uk.
authors: Tomáš
authors: T
authors: Hanke
authors: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. BClotet@irsicaixa.es.|'Lluita contra la Sida' Foundation, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain. BClotet@irsicaixa.es.|Universitat de Vic-Universitat Central de Catalunya (UVic-UCC), Vic, Spain. BClotet@irsicaixa.es.|Universitat Autònoma de Barcelona, Barcelona, Spain. BClotet@irsicaixa.es.
authors: Bonaventura
authors: B
authors: Clotet
authors: Human Retrovirus Section, National Cancer Institute-Frederick, Frederick, MD, USA. george.pavlakis@nih.gov.
authors: George N
authors: GN
authors: Pavlakis
authors: Human Retrovirus Pathogenesis Section, National Cancer Institute-Frederick, Frederick, MD, USA. barbara.felber@nih.gov.
authors: Barbara K
authors: BK
authors: Felber
authors: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. cbrander@irsicaixa.es.|Universitat de Vic-Universitat Central de Catalunya (UVic-UCC), Vic, Spain. cbrander@irsicaixa.es.|Universitat Autònoma de Barcelona, Barcelona, Spain. cbrander@irsicaixa.es.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. cbrander@irsicaixa.es.
authors: Christian
authors: C
authors: Brander
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015331:Cohort Studies; D000939:Epitopes / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D057809:HEK293 Cells; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000276:immunology*; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007156:Immunologic Memory; D008253:Macaca mulatta; D008297:Male; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014611:Vaccination
chemical_list: D016915:AIDS Vaccines; D000998:Antiviral Agents; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D010455:Peptides