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Long-term programming of antigen-specific immunity from gene expression signatures in the PBMC of rhesus macaques immunized with an SIV DNA vaccine.

Belisle SE, Yin J, Shedlock DJ, Dai A, Yan J, Hirao L, Kutzler MA, Lewis MG, Andersen H, Lank SM, Karl JA, O'Connor DH, Khan A, Sardesai N, Chang J, Aicher L, Palermo RE, Weiner DB, Katze MG, Boyer J - PLoS ONE (2011)

Bottom Line: We observed that the RANTES-adjuvanted animals were significantly better at suppressing viral replication during chronic infection and exhibited a distinct pattern of gene expression which included immune cell-trafficking and cell cycle genes.Furthermore, a greater percentage of vaccine-induced central memory CD8+ T-cells capable of an activated phenotype were detected in these animals as measured by activation analysis.Thus, co-immunization with the RANTES molecular adjuvant followed by EP led to the generation of cellular immunity that was transcriptionally distinct and had a greater protective efficacy than its DNA alone counterpart.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
While HIV-1-specific cellular immunity is thought to be critical for the suppression of viral replication, the correlates of protection have not yet been determined. Rhesus macaques (RM) are an important animal model for the study and development of vaccines against HIV/AIDS. Our laboratory has helped to develop and study DNA-based vaccines in which recent technological advances, including genetic optimization and in vivo electroporation (EP), have helped to dramatically boost their immunogenicity. In this study, RMs were immunized with a DNA vaccine including individual plasmids encoding SIV gag, env, and pol alone, or in combination with a molecular adjuvant, plasmid DNA expressing the chemokine ligand 5 (RANTES), followed by EP. Along with standard immunological assays, flow-based activation analysis without ex vivo restimulation and high-throughput gene expression analysis was performed. Strong cellular immunity was induced by vaccination which was supported by all assays including PBMC microarray analysis that identified the up-regulation of 563 gene sequences including those involved in interferon signaling. Furthermore, 699 gene sequences were differentially regulated in these groups at peak viremia following SIVmac251 challenge. We observed that the RANTES-adjuvanted animals were significantly better at suppressing viral replication during chronic infection and exhibited a distinct pattern of gene expression which included immune cell-trafficking and cell cycle genes. Furthermore, a greater percentage of vaccine-induced central memory CD8+ T-cells capable of an activated phenotype were detected in these animals as measured by activation analysis. Thus, co-immunization with the RANTES molecular adjuvant followed by EP led to the generation of cellular immunity that was transcriptionally distinct and had a greater protective efficacy than its DNA alone counterpart. Furthermore, activation analysis and high-throughput gene expression data may provide better insight into mechanisms of viral control than may be observed using standard immunological assays.

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Vaccination is associated with decrease in the expression of cell death related networks at peak viremia.IPA network indicate the relationship between differentially expressed genes related to cell death as determined from analysis of the 539 genes that significantly distinguished the treatment groups only at peak viremia by ANOVA. Molecule shading reflects the average log-ratio of expression for (A) Control, (B) DNA, and (C) DNA+RANTES groups at ten days post-SIV challenge. Red represents an average increase in expression and green represents a decrease.
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pone-0019681-g009: Vaccination is associated with decrease in the expression of cell death related networks at peak viremia.IPA network indicate the relationship between differentially expressed genes related to cell death as determined from analysis of the 539 genes that significantly distinguished the treatment groups only at peak viremia by ANOVA. Molecule shading reflects the average log-ratio of expression for (A) Control, (B) DNA, and (C) DNA+RANTES groups at ten days post-SIV challenge. Red represents an average increase in expression and green represents a decrease.

Mentions: We next examined the genes that distinguished the groups only at peak viremia (Table S3). Differences in the expression of these genes reflect long-term reprogramming of response to SIVpol which is evident concurrent with the vast immunological insult of SIV challenge. Interestingly, at peak viremia, vaccination was associated with a decrease in the expression of cell death-related genes following SIVpol-stimulation (Figure 9).


Long-term programming of antigen-specific immunity from gene expression signatures in the PBMC of rhesus macaques immunized with an SIV DNA vaccine.

Belisle SE, Yin J, Shedlock DJ, Dai A, Yan J, Hirao L, Kutzler MA, Lewis MG, Andersen H, Lank SM, Karl JA, O'Connor DH, Khan A, Sardesai N, Chang J, Aicher L, Palermo RE, Weiner DB, Katze MG, Boyer J - PLoS ONE (2011)

Vaccination is associated with decrease in the expression of cell death related networks at peak viremia.IPA network indicate the relationship between differentially expressed genes related to cell death as determined from analysis of the 539 genes that significantly distinguished the treatment groups only at peak viremia by ANOVA. Molecule shading reflects the average log-ratio of expression for (A) Control, (B) DNA, and (C) DNA+RANTES groups at ten days post-SIV challenge. Red represents an average increase in expression and green represents a decrease.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3119060&req=5

pone-0019681-g009: Vaccination is associated with decrease in the expression of cell death related networks at peak viremia.IPA network indicate the relationship between differentially expressed genes related to cell death as determined from analysis of the 539 genes that significantly distinguished the treatment groups only at peak viremia by ANOVA. Molecule shading reflects the average log-ratio of expression for (A) Control, (B) DNA, and (C) DNA+RANTES groups at ten days post-SIV challenge. Red represents an average increase in expression and green represents a decrease.
Mentions: We next examined the genes that distinguished the groups only at peak viremia (Table S3). Differences in the expression of these genes reflect long-term reprogramming of response to SIVpol which is evident concurrent with the vast immunological insult of SIV challenge. Interestingly, at peak viremia, vaccination was associated with a decrease in the expression of cell death-related genes following SIVpol-stimulation (Figure 9).

Bottom Line: We observed that the RANTES-adjuvanted animals were significantly better at suppressing viral replication during chronic infection and exhibited a distinct pattern of gene expression which included immune cell-trafficking and cell cycle genes.Furthermore, a greater percentage of vaccine-induced central memory CD8+ T-cells capable of an activated phenotype were detected in these animals as measured by activation analysis.Thus, co-immunization with the RANTES molecular adjuvant followed by EP led to the generation of cellular immunity that was transcriptionally distinct and had a greater protective efficacy than its DNA alone counterpart.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
While HIV-1-specific cellular immunity is thought to be critical for the suppression of viral replication, the correlates of protection have not yet been determined. Rhesus macaques (RM) are an important animal model for the study and development of vaccines against HIV/AIDS. Our laboratory has helped to develop and study DNA-based vaccines in which recent technological advances, including genetic optimization and in vivo electroporation (EP), have helped to dramatically boost their immunogenicity. In this study, RMs were immunized with a DNA vaccine including individual plasmids encoding SIV gag, env, and pol alone, or in combination with a molecular adjuvant, plasmid DNA expressing the chemokine ligand 5 (RANTES), followed by EP. Along with standard immunological assays, flow-based activation analysis without ex vivo restimulation and high-throughput gene expression analysis was performed. Strong cellular immunity was induced by vaccination which was supported by all assays including PBMC microarray analysis that identified the up-regulation of 563 gene sequences including those involved in interferon signaling. Furthermore, 699 gene sequences were differentially regulated in these groups at peak viremia following SIVmac251 challenge. We observed that the RANTES-adjuvanted animals were significantly better at suppressing viral replication during chronic infection and exhibited a distinct pattern of gene expression which included immune cell-trafficking and cell cycle genes. Furthermore, a greater percentage of vaccine-induced central memory CD8+ T-cells capable of an activated phenotype were detected in these animals as measured by activation analysis. Thus, co-immunization with the RANTES molecular adjuvant followed by EP led to the generation of cellular immunity that was transcriptionally distinct and had a greater protective efficacy than its DNA alone counterpart. Furthermore, activation analysis and high-throughput gene expression data may provide better insight into mechanisms of viral control than may be observed using standard immunological assays.

Show MeSH
Related in: MedlinePlus