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Safety and immunogenicity of therapeutic DNA vaccination in individuals treated with antiretroviral therapy during acute/early HIV-1 infection.

ABSTRACT: An effective therapeutic vaccine that could augment immune control of HIV-1 replication may abrogate or delay the need for antiretroviral therapy. AIDS Clinical Trials Group (ACTG) A5187 was a phase I/II, randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of an HIV-1 DNA vaccine (VRC-HVDNA 009-00-VP) in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. (clinicaltrials.gov NCT00125099)Twenty healthy HIV-1 infected subjects who were treated with antiretroviral therapy during acute/early HIV-1 infection and had HIV-1 RNA<50 copies/mL were randomized to receive either vaccine or placebo. The objectives of this study were to evaluate the safety and immunogenicity of the vaccine. Following vaccination, subjects interrupted antiretroviral treatment, and set-point HIV-1 viral loads and CD4 T cell counts were determined 17-23 weeks after treatment discontinuation.Twenty subjects received all scheduled vaccinations and discontinued antiretroviral therapy at week 30. No subject met a primary safety endpoint. No evidence of differences in immunogenicity were detected in subjects receiving vaccine versus placebo. There were also no significant differences in set-point HIV-1 viral loads or CD4 T cell counts following treatment discontinuation. Median set-point HIV-1 viral loads after treatment discontinuation in vaccine and placebo recipients were 3.5 and 3.7 log(10) HIV-1 RNA copies/mL, respectively.The HIV-1 DNA vaccine (VRC-HIVDNA 009-00-VP) was safe but poorly immunogenic in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. Viral set-points were similar between vaccine and placebo recipients following treatment interruption. However, median viral load set-points in both groups were lower than in historical controls, suggesting a possible role for antiretroviral therapy in persons with acute or early HIV-1 infection and supporting the safety of discontinuing treatment in this group.Clinicaltrials.gov NCT00125099.

SUBMITTER: Rosenberg ES

PROVIDER: S-EPMC2866663 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Safety and immunogenicity of therapeutic DNA vaccination in individuals treated with antiretroviral therapy during acute/early HIV-1 infection.

Rosenberg Eric S ES Graham Barney S BS Chan Ellen S ES Bosch Ronald J RJ Stocker Vicki V Maenza Janine J Markowitz Martin M Little Susan S Sax Paul E PE Collier Ann C AC Nabel Gary G Saindon Suzanne S Flynn Theresa T Kuritzkes Daniel D Barouch Dan H DH

PloS one 20100510 5

<h4>Background</h4>An effective therapeutic vaccine that could augment immune control of HIV-1 replication may abrogate or delay the need for antiretroviral therapy. AIDS Clinical Trials Group (ACTG) A5187 was a phase I/II, randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of an HIV-1 DNA vaccine (VRC-HVDNA 009-00-VP) in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. (clinicaltrials.gov NCT00125099)<h4>Methods</h4>Twe ...[more]

PMID: 20479938

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Project description:Introduction: Systems vaccinology is a novel approach to predict immune response in vaccines. We have used a systems biology approach to identify early gene ‘signatures’ that predicted viral load control after analytical therapy interruption (ATI) in HIV-1 infected patients vaccinated with a dendritic cell-based (DC) HIV-1 vaccine. Methods: Frozen post-vaccination PBMC samples from participants of a previously published DC vaccine (DCV2) clinical trial were used for the study. mRNA and miRNA were extracted and gene expression was determined by microarray method. Differential gene expression analysis was performed on both mRNA and miRNA between responders (> 1 log10 copies/mL drop of VL after 12 weeks of ATI) and non-responders (<= 1 log10 copies/mL drop in VL at week 12 of ATI). Gene set enrichment analysis (GSEA) was carried out with the hallmark gene sets of the Broad Institute on the mRNA data. After the stand-alone analyses of mRNA and miRNA we performed an additional GSEA with gene sets defined by the genes regulated by significantly differentially expressed miRNAs. Statistical analysis was done using R and the GSEA software of the Broad Institute. Results: There were 15 responders and 20 non-responders. No differentially expressed mRNAs were observed between responders and non-responders. As compared with non-responders, responders showed an up-regulation of gene sets corresponding to TNF- alpha signaling via the NFkB pathway, inflammatory response, coagulation, the complement system, Il6 and Il2 JAK-STAT signaling, or reactive oxygen-species pathways were up-regulated, and a down-regulation of gene sets corresponding to E2F targets, oxidative phosphorylation, or interferon alpha response. We found 9 differentially expressed miRNAs between responders and non-responders: miR-32-3p, miR-185-3p, miR-223-3p, miR-500b-3p, miR-550a-3p, miR-1183, miR-1184, miR-4455, and miR-8063. Twelve Broad hallmark gene sets that were significantly deregulated in the GSEA showed significant overlap with genes regulated by one or more of these miRNAs, 10 of them with genes regulated by miR-223-3p. We also observed that the expression of genes regulated by miR-223-3p, miR-1183 and miR-8063 was significantly down-regulated in responders as compared with non-responders. Conclusions: Deregulation of certain gene sets related to inflammatory processes seems fundamental in viral control during ATI. miR-223-3p may be one of the miRNAs that fine tune part of these processes.

Dataset Information

Safety and immunogenicity of therapeutic DNA vaccination in individuals treated with antiretroviral therapy during acute/early HIV-1 infection.

Publications

Safety and immunogenicity of therapeutic DNA vaccination in individuals treated with antiretroviral therapy during acute/early HIV-1 infection.

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