The comparsion of gene expression in ALVAC- and Ad5-infected human monocyte-derived dendritic cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE103204 | GEO | 2017/09/27
SECONDARY ACCESSION(S): PRJNA400483
REPOSITORIES: GEO
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Project description:Viral vectors are attractive vaccine platforms that elicit robust innate and adaptive immune responses; however, viral vector vaccine candidates vary greatly in their ability to induce protective immunity. Ad5 vectors elicit robust CD8+ T cell responses but typically characterized by an exhausted phenotype. The mechanisms by which Ad5 vectors induce dysfunctional CD8+ T cells have not been fully elucidated. Here we demonstrate that Ad5 vectors, but not Ad26 vectors, elicit exhausted antigen-specific IL-10+PD1+ CD4+ T cells with a dysfunctional transcriptional profile, and these cells effectively suppress CD8+ T cells responses in vivo. Induction of inhibitory CD4+ T cells by Ad5 vectors was associated with increased IL-27 expression, and IL-27 blockade improved CD4+ T cell polyfunctionality. Together our data highlight a novel role for IL-27 in regulating responses to viral vector vaccines. Splenic CD45.2+ OT-II TCR-Tg CD4 T cells from CD45.1+ B6 mice immunized with Ad5-OVA or Ad26-OVA were purified by FACS on day 10 post-immunization
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Project description:The RV144 HIV vaccine trial remains the only study to demonstrate significant protection from future HIV-1 acquisition. One of the key components of the RV144 vaccine was the use of the canarypox vector ALVAC as the priming component. Since AIDSVAX, the booster component, alone failed to provide protection we hypothesized that the ALVAC prime contributed significantly to the generation of protection. To test this, we designed a NHP immunogenicity trial to mechanistically link ALVAC vaccination with the magnitude of V1V2 titers, the most significant immune correlate of reduced HIV-1 acquisition in RV144. Our objective was to use a systems biology approach to identify the transcription factors, target genes and immune pathways which were being induced by ALVAC vaccination and associated with higher V1V2 titers. We identified the transcription factor CREB1 and its target genes as rapidly induced by ALVAC in multiple immune subsets and that CREB1 drives the expression and activation of a network of other TFs which are critical for modulating immune responses. Pathways induced by this ALVAC-CREB1 axis include lymphocyte/leukocyte migration, lymphocyte differentiation, antigen processing and presentation, T cell co-stimulation and cytokine signaling.
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Project description:To better understand how innate immune responses to vaccination can lead to lasting protective immunity, we used a systems approach to define immune signatures in humans over 1 wk following MRKAd5/HIV vaccination that predicted subsequent HIV-specific T-cell responses. Within 24 h, striking increases in peripheral blood mononuclear cell gene expression associated with inflammation, IFN response, and myeloid cell trafficking occurred, and lymphocyte-specific transcripts decreased. These alterations were corroborated by marked serum inflammatory cytokine elevations and egress of circulating lymphocytes. Responses of vaccinees with preexisting adenovirus serotype 5 (Ad5) neutralizing antibodies were strongly attenuated, suggesting that enhanced HIV acquisition in Ad5-seropositive subgroups in the Step Study may relate to the lack of appropriate innate activation rather than to increased systemic immune activation. Importantly, patterns of chemoattractant cytokine responses at 24 h and alterations in 209 peripheral blood mononuclear cell transcripts at 72 h were predictive of subsequent induction and magnitude of HIV-specific CD8(+) T-cell responses. This systems approach provides a framework to compare innate responses induced by vectors, as shown here by contrasting the more rapid, robust response to MRKAd5/HIV with that to yellow fever vaccine. When applied iteratively, the findings may permit selection of HIV vaccine candidates eliciting innate immune response profiles more likely to drive HIV protective immunity. This SuperSeries is composed of the SubSeries listed below.
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Project description:The RV144 HIV vaccine trial remains the only study to demonstrate significant protection from future HIV-1 acquisition. One of the key components of the RV144 vaccine was the use of the canarypox vector ALVAC as the priming component. Since AIDSVAX, the booster component, alone failed to provide protection we hypothesized that the ALVAC prime contributed significantly to the generation of protection. To test this, we designed a NHP immunogenicity trial to mechanistically link ALVAC vaccination with the magnitude of V1V2 titers, the most significant immune correlate of reduced HIV-1 acquisition in RV144. Our objective was to use a systems biology approach to identify the transcription factors, target genes and immune pathways which were being induced by ALVAC vaccination and associated with higher V1V2 titers. We identified the transcription factor CREB1 and its target genes as rapidly induced by ALVAC in multiple immune subsets and that CREB1 drives the expression and activation of a network of other TFs which are critical for modulating immune responses. Pathways induced by this ALVAC-CREB1 axis include lymphocyte/leukocyte migration, lymphocyte differentiation, antigen processing and presentation, T cell co-stimulation and cytokine signaling.
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Project description:The RV144 HIV vaccine trial remains the only study to demonstrate significant protection from future HIV-1 acquisition. One of the key components of the RV144 vaccine was the use of the canarypox vector ALVAC as the priming component. Since AIDSVAX, the booster component, alone failed to provide protection we hypothesized that the ALVAC prime contributed significantly to the generation of protection. To test this, we designed a NHP immunogenicity trial to mechanistically link ALVAC vaccination with the magnitude of V1V2 titers, the most significant immune correlate of reduced HIV-1 acquisition in RV144. Our objective was to use a systems biology approach to identify the transcription factors, target genes and immune pathways which were being induced by ALVAC vaccination and associated with higher V1V2 titers. We identified the transcription factor CREB1 and its target genes as rapidly induced by ALVAC in multiple immune subsets and that CREB1 drives the expression and activation of a network of other TFs which are critical for modulating immune responses. Pathways induced by this ALVAC-CREB1 axis include lymphocyte/leukocyte migration, lymphocyte differentiation, antigen processing and presentation, T cell co-stimulation and cytokine signaling.
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