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J Transl Med. 2015 Feb 15;13:60. doi: 10.1186/s12967-015-0392-5.

A human immune data-informed vaccine concept elicits strong and broad T-cell specificities associated with HIV-1 control in mice and macaques.

Author information

1
IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. bmothe@irsicaixa.es.
2
'Lluita contra la Sida' Foundation, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain. bmothe@irsicaixa.es.
3
Universitat de Vic-Universitat Central de Catalunya (UVic-UCC), Vic, Spain. bmothe@irsicaixa.es.
4
Human Retrovirus Pathogenesis Section, National Cancer Institute-Frederick, Frederick, MD, USA. xintao.hu@nih.gov.
5
IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. ALlano@irsicaixa.es.
6
Human Retrovirus Section, National Cancer Institute-Frederick, Frederick, MD, USA. margherita.rosati@nih.gov.
7
IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. aolvera@irsicaixa.es.
8
Human Retrovirus Pathogenesis Section, National Cancer Institute-Frederick, Frederick, MD, USA. kviraj@gmail.com.
9
Human Retrovirus Section, National Cancer Institute-Frederick, Frederick, MD, USA. antonio.valentin@nih.gov.
10
Human Retrovirus Pathogenesis Section, National Cancer Institute-Frederick, Frederick, MD, USA. candido.alicea@nih.gov.
11
Human Retrovirus Pathogenesis Section, National Cancer Institute-Frederick, Frederick, MD, USA. guy.pilkington@nih.gov.
12
Inovio Pharmaceuticals Inc, Blue Bell, PA, USA. nsardesai@inovio.com.
13
IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. mrocafort@irsicaixa.es.
14
HIV Unit, Hospital de la Vall d'Hebrón, Barcelona, Spain. mcrespo@vhebron.net.
15
IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. jcarrillo@irsicaixa.es.
16
Centres Penitenciaris BCN, Barcelona, Spain. amarco@aspb.cat.
17
University of Washington, Seattle, WA, USA. jmullins@u.washington.edu.
18
Nuffield Department of Medicine, University of Oxford, The John Radcliffe Hospital, Oxford, UK. lucy.dorrell@ndm.ox.ac.uk.
19
The Jenner Institute, University of Oxford, Oxford, UK. tomas.hanke@ndm.ox.ac.uk.
20
IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. BClotet@irsicaixa.es.
21
'Lluita contra la Sida' Foundation, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain. BClotet@irsicaixa.es.
22
Universitat de Vic-Universitat Central de Catalunya (UVic-UCC), Vic, Spain. BClotet@irsicaixa.es.
23
Universitat Autònoma de Barcelona, Barcelona, Spain. BClotet@irsicaixa.es.
24
Human Retrovirus Section, National Cancer Institute-Frederick, Frederick, MD, USA. george.pavlakis@nih.gov.
25
Human Retrovirus Pathogenesis Section, National Cancer Institute-Frederick, Frederick, MD, USA. barbara.felber@nih.gov.
26
IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i Pujol, Crta Canyet s/n., 08916, Badalona, Barcelona, Spain. cbrander@irsicaixa.es.
27
Universitat de Vic-Universitat Central de Catalunya (UVic-UCC), Vic, Spain. cbrander@irsicaixa.es.
28
Universitat Autònoma de Barcelona, Barcelona, Spain. cbrander@irsicaixa.es.
29
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. cbrander@irsicaixa.es.

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.

PMID:
25879820
PMCID:
PMC4336696
DOI:
10.1186/s12967-015-0392-5
[Indexed for MEDLINE]
Free PMC Article

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