A human immune data-informed vaccine concept elicits strong and broad T-cell specificities associated with HIV-1 control in mice and macaques
Mothe, Beatriz (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Hu, Xintao (National Cancer Institute at Frederick (Frederick, Estats Units d'Amèrica))
Llano Montero, Anuska (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Rosati, Margherita (National Cancer Institute at Frederick (Frederick, Estats Units d'Amèrica))
Olvera, Alex (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Kulkarni, Viraj (National Cancer Institute at Frederick (Frederick, Estats Units d'Amèrica))
Valentin, Antonio (National Cancer Institute at Frederick (Frederick, Estats Units d'Amèrica))
Alicea, Cándido (National Cancer Institute at Frederick (Frederick, Estats Units d'Amèrica))
Pilkington, Guy R. (National Cancer Institute at Frederick (Frederick, Estats Units d'Amèrica))
Sardesai, Niranjan Y. (Inovio Pharmaceuticals)
Rocafort, Muntsa (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Crespo Casal, Manuel (Hospital Universitari Vall d'Hebron)
Carrillo, Jorge (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Marco, Andrés (Centre Penitenciari d'Homes (Barcelona, Catalunya))
Mullins, James I. (University of Washington (Estats Units d'Amèrica))
Dorrell, Lucy (John Radcliffe Hospital (Oxford, Regne Unit))
Hanke, Tomáš (University of Oxford (Regne Unit))
Clotet Sala, Bonaventura (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Pavlakis, George N. (National Cancer Institute at Frederick (Frederick, Estats Units d'Amèrica))
Felber, Barbara K. (National Cancer Institute at Frederick (Frederick, Estats Units d'Amèrica))
Brander, Christian (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Universitat Autònoma de Barcelona

Date:	2015
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.
Grants:	European Commission 241904 Instituto de Salud Carlos III CM08/00020 Instituto de Salud Carlos III JR13/00024
Note:	Altres ajuts: MTM/2008-06747-C02-00
Note:	Altres ajuts: FIPSE/36-0737-0
Note:	Altres ajuts: P01AI057005
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	VIH (Virus) ; Immunitat ; HIV-1 T-cell immunogen ; HIV-1 specific CTL ; HLA ; Immunogenicity ; Subdominant ; Viral fitness ; CTL escape ; T-helper epitope ; Population coverage
Published in:	Journal of translational medicine, Vol. 13 Núm. 60 (february 2015) , ISSN 1479-5876

DOI: 10.1186/s12967-015-0392-5
PMID: 25879820

23 p, 3.3 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles