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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    • "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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