ABSTRACT
With the human immunodeficiency virus type 1 (HIV-1) epidemic expanding at increasing speed, development of a safe and effective vaccine remains a high priority. One of the most central vaccine platforms considered is plasmid DNA. However, high doses of DNA and several immunizations are typically needed to achieve detectable T-cell responses. In this study, a Semliki Forest virus replicon DNA vaccine designed for human clinical trials, DREP.HIVA, encoding an antigen that is currently being used in human trials in the context of a conventional DNA plasmid, pTHr.HIVA, was generated. It was shown that a single immunization of DREP.HIVA stimulated HIV-1-specific T-cell responses in mice, suggesting that the poor immunogenicity of conventional DNA vaccines may be enhanced by using viral replicon-based plasmid systems. The results presented here support the evaluation of Semliki Forest virus replicon DNA vaccines in non-human primates and in clinical studies.
Subject(s)
DNA, Viral/immunology , HIV Infections/prevention & control , HIV-1/immunology , Semliki forest virus/immunology , Vaccination , Viral Vaccines/immunology , Animals , Drug Evaluation, Preclinical , Female , HIV Infections/blood , Mice , Mice, Inbred BALB C , Replicon/immunology , Semliki forest virus/genetics , T-Lymphocytes/immunology , Vaccines, DNA/immunology , Viral Vaccines/administration & dosageABSTRACT
The RNA genomes of alphaviruses have been exploited to create highly efficient vectors for transient expression of foreign genes in mammalian cells and for use as vehicles for genetic vaccines. For Semliki Forest virus (SFV), a representative alphavirus, three strategies for in vitro and in vivo gene-delivery have been developed. One method relies on the packaging of recombinant vectors into suicidal viral particles and infection of target cells, whereas the other two methods are based on direct transfection of target cells, either by using naked DNA encoding the SFV replicon placed downstream of an RNA polymerase II dependent promoter, or by using in vitro transcribed RNA encoding the SFV replicon. All three approaches result in the delivery of a selfreplicating SFV vector into target cells, with expression of foreign genes being driven from a highly efficient viral subgenomic promoter.
