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Transient IL-10 receptor blockade can enhance CD8(+) T cell responses to a simian adenovirus-vectored HIV-1 conserved region immunogen.

ABSTRACT: Viral vector vaccines designed to elicit CD8(+) T cells in non-human primates exert potent control of immunodeficiency virus infections; however, similar approaches have been unsuccessful in humans. Adenoviral vectors elicit potent T cell responses but also induce production of immunosuppressive interleukin-10 (IL-10), which can limit the expansion of T cell responses. We investigated whether inhibiting IL-10 signaling prior to immunization with a candidate adenovirus vectored-HIV-1 vaccine, ChAdV63.HIVconsv, could modulate innate and adaptive immune responses in BALB/c mice. Transient IL-10 receptor blockade led to a modest but significant increase in the total magnitude CD8(+) T cell response to HIVconsv, but did not affect T cell responses to immunodominant epitopes. Anti-IL-10R-treated animals also exhibited greater expression of CD86 on CD11c(+) dendritic cells. Our data support further investigation and optimization of IL-10 blocking strategies to improve the immunogenicity of vaccines based on replication-defective adenoviruses.

SUBMITTER: Clutton G

PROVIDER: S-EPMC4514343 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Transient IL-10 receptor blockade can enhance CD8(+) T cell responses to a simian adenovirus-vectored HIV-1 conserved region immunogen.

Clutton Genevieve G Bridgeman Anne A Reyes-Sandoval Arturo A Hanke Tomas T Dorrell Lucy L

Human vaccines & immunotherapeutics 20150101 4

Viral vector vaccines designed to elicit CD8(+) T cells in non-human primates exert potent control of immunodeficiency virus infections; however, similar approaches have been unsuccessful in humans. Adenoviral vectors elicit potent T cell responses but also induce production of immunosuppressive interleukin-10 (IL-10), which can limit the expansion of T cell responses. We investigated whether inhibiting IL-10 signaling prior to immunization with a candidate adenovirus vectored-HIV-1 vaccine, ChA ...[more]

PMID: 25751015

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Project description:BackgroundHepatitis C virus (HCV) genomic variability is a major challenge to the generation of a prophylactic vaccine. We have previously shown that HCV specific T-cell responses induced by a potent T-cell vaccine encoding a single strain subtype-1b immunogen target epitopes dominant in natural infection. However, corresponding viral regions are highly variable at a population level, with a reduction in T-cell reactivity to these variants. We therefore designed and manufactured second generation simian adenovirus vaccines encoding genomic segments, conserved between viral genotypes and assessed these for immunogenicity.MethodsWe developed a computer algorithm to identify HCV genomic regions that were conserved between viral subtypes. Conserved segments below a pre-defined diversity threshold spanning the entire HCV genome were combined to create novel immunogens (1000-1500 amino-acids), covering variation in HCV subtypes 1a and 1b, genotypes 1 and 3, and genotypes 1-6 inclusive. Simian adenoviral vaccine vectors (ChAdOx) encoding HCV conserved immunogens were constructed. Immunogenicity was evaluated in C57BL6 mice using panels of genotype-specific peptide pools in ex-vivo IFN-ϒ ELISpot and intracellular cytokine assays.ResultsChAdOx1 conserved segment HCV vaccines primed high-magnitude, broad, cross-reactive T-cell responses; the mean magnitude of total HCV specific T-cell responses was 1174 SFU/106 splenocytes for ChAdOx1-GT1-6 in C57BL6 mice targeting multiple genomic regions, with mean responses of 935, 1474 and 1112 SFU/106 against genotype 1a, 1b and 3a peptide panels, respectively. Functional assays demonstrated IFNg and TNFa production by vaccine-induced CD4 and CD8 T-cells. In silico analysis shows that conserved immunogens contain multiple epitopes, with many described in natural HCV infection, predicting immunogenicity in humans.ConclusionsSimian adenoviral vectored vaccines encoding genetic segments that are conserved between all major HCV genotypes contain multiple T-cell epitopes and are highly immunogenic in pre-clinical models. These studies pave the way for the assessment of multi-genotypic HCV T-cell vaccines in humans.

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Transient IL-10 receptor blockade can enhance CD8(+) T cell responses to a simian adenovirus-vectored HIV-1 conserved region immunogen.

Publications

Transient IL-10 receptor blockade can enhance CD8(+) T cell responses to a simian adenovirus-vectored HIV-1 conserved region immunogen.

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