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Título:
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A human immune data-informed vaccine concept elicits strong and broad T-cell specificities associated with HIV-1 control in mice and macaques
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Autor/a:
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Mothe, B.; Hu, Xintao; Llano, Anuska; Rosati, Margherita; Olvera, Alex; Kulkarni, Viraj; Valentin, Antonio; Alicea, Candido; Pilkington, Guy R.; Sardesai, Niranjan J.; Rocafort, Muntsa; Crespo, Manel; Carrillo, Jorge; Marco, Andrés; Mullins, James I.; Dorrell, Lucy; Hanke, Thomas; Clotet, Bonaventura; Pavlakis, George N.; Felber, Barbara; Brander, Christian
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Otros autores:
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Universitat de Vic - Universitat Central de Catalunya. Càtedra de la Sida i Malalties Relacionades |
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Notas:
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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. |
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Materia(s):
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-VIH (Virus)
-Antígens HLA
-Immunogenètica
-Sida -- Tractament |
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Derechos:
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Aquest document està subjecte a aquesta llicència Creative Commons
http://creativecommons.org/licenses/by/3.0/es/
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Tipo de documento:
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Artículo
info:eu-repo/publishedVersion |
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Editor:
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BioMed Central
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