A Human T-Cell Leukemia Virus Type 1 Regulatory Element Enhances the Immunogenicity of Human Immunodeficiency Virus Type 1 DNA Vaccines in Mice and Nonhuman Primates

Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Journal of Virology (Impact Factor: 4.44). 08/2005; 79(14):8828-34. DOI: 10.1128/JVI.79.14.8828-8834.2005
Source: PubMed


Plasmid DNA vaccines elicit potent and protective immune responses in numerous small-animal models of infectious diseases. However, their immunogenicity in primates appears less potent. Here we investigate a novel approach that optimizes regulatory elements in the plasmid backbone to improve the immunogenicity of DNA vaccines. Among various regions analyzed, we found that the addition of a regulatory sequence from the R region of the long terminal repeat from human T-cell leukemia virus type 1 (HTLV-1) to the cytomegalovirus (CMV) enhancer/promoter increased transgene expression 5- to 10-fold and improved cellular immune responses to human immunodeficiency virus type 1 (HIV-1) antigens. In cynomolgus monkeys, DNA vaccines containing the CMV enhancer/promoter with the HTLV-1 R region (CMV/R) induced markedly higher cellular immune responses to HIV-1 Env from clades A, B, and C and to HIV-1 Gag-Pol-Nef compared with the parental DNA vaccines. These data demonstrate that optimization of specific regulatory elements can substantially improve the immunogenicity of DNA vaccines encoding multiple antigens in small animals and in nonhuman primates. This strategy could therefore be explored as a potential method to enhance DNA vaccine immunogenicity in humans.

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Available from: Birgit Korioth-Schmitz, Oct 05, 2015
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    • "One contained the CN54 Env transgene and the other a Gag-Pol-Nef genetic fusion construct. Both plasmids utilized CMV enhancer/promoter with a human T-cell leukemia type 1 regulatory element to drive transgene expression [41]. The MVA pox vector was created by Prof. Mariano Esteban (CSIC, Spain) and expresses the CN54gp120 Env and the Gag-Pol-Nef polyprotein from two back-to-back synthetic Early/Late transcriptional promoters [42], [43]. "
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    ABSTRACT: Using a unique vaccine antigen matched and single HIV Clade C approach we have assessed the immunogenicity of a DNA-poxvirus-protein strategy in mice and rabbits, administering MVA and protein immunizations either sequentially or simultaneously and in the presence of a novel TLR4 adjuvant, GLA-AF. Mice were vaccinated with combinations of HIV env/gag-pol-nef plasmid DNA followed by MVA-C (HIV env/gag-pol-nef) with HIV CN54gp140 protein (+/-GLA-AF adjuvant) and either co-administered in different muscles of the same animal with MVA-C or given sequentially at 3-week intervals. The DNA prime established a population of B cells that were able to mount a statistically significant anamnestic response to the boost vaccines. The greatest antigen-specific antibody response was observed in animals that received all vaccine components. Moreover, a high proportion of the total mucosal IgG (20 - 50%) present in the vaginal vault of these vaccinated animals was vaccine antigen-specific. The potent elicitation of antigen-specific immune responses to this vaccine modality was also confirmed in rabbits. Importantly, co-administration of MVA-C with the GLA-AF adjuvanted HIV CN54gp140 protein significantly augmented the antigen-specific T cell responses to the Gag antigen, a transgene product expressed by the MVA-C vector in a separate quadriceps muscle. We have demonstrated that co-administration of MVA and GLA-AF adjuvanted HIV CN54gp140 protein was equally effective in the generation of humoral responses as a sequential vaccination modality thus shortening and simplifying the immunization schedule. In addition, a significant further benefit of the condensed vaccination regime was that T cell responses to proteins expressed by the MVA-C were potently enhanced, an effect that was likely due to enhanced immunostimulation in the presence of systemic GLA-AF.
    PLoS ONE 01/2014; 9(1):e84707. DOI:10.1371/journal.pone.0084707 · 3.23 Impact Factor
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    • "Most of the transactivator genes that have been evaluated thus far have viral origins, such as the regulatory R region from the 5′ long terminal repeat (LTR) of human T-cell leukemia virus type 1 (HTLV-1). This particular element, combined with a CMV promoter, has been shown to induce a suggestively higher cellular immune response to HIV-1 compared to the analogous parental DNA vaccines in both mice and non-human primates (54). Despite promising results, the use of such regulatory enhancers is of some concern for off target effects and will need additional investigation. "
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    Frontiers in Immunology 11/2013; 4:354. DOI:10.3389/fimmu.2013.00354
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    • "The plasmid pVRC-grttnC (manufactured by Aldevron, Fargo, ND, USA) expresses an HIV-1 subtype C polyprotein consisting of Gag, RT, Tat and Nef (grttn) and is a second generation DNA vaccine. It differs from the first generation vaccine pTHgrttnC [33] in that the pTH vector backbone has been replaced with the pVRC backbone provided by the Vaccine Research Center of the National Institutes of Health, Bethesda, Maryland, USA [34]. The HIV-1 genes (grttn) were modified for safety issues, codon optimized for human expression [33] and cloned downstream of the cytomegalovirus AD169 immediate-early promoter, with an enhancer intron A and a Kozak sequence. "
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