Abstract
In an effort to make affordable vaccines suitable for the regions most affected by HIV-1, we have constructed stable vaccines that express an HIV-1 subtype C mosaic Gag immunogen (BCG-GagM, MVA-GagM and DNA-GagM). Mosaic immunogens have been designed to address the tremendous diversity of this virus. Here we have shown that GagM buds from cells infected and transfected with MVA-GagM and DNA-GagM respectively and forms virus-like particles. Previously we showed that a BCG-GagM prime MVA-GagM boost generated strong cellular immune responses in mice. In this study immune responses to the DNA-GagM and MVA-GagM vaccines were evaluated in homologous and heterologous prime-boost vaccinations. The DNA homologous prime boost vaccination elicited predominantly CD8+ T cells while the homologous MVA vaccination induced predominantly CD4+ T cells. A heterologous DNA-GagM prime MVA-GagM boost induced strong, more balanced Gag CD8+ and CD4+ T cell responses and that were predominantly of an effector memory phenotype. The immunogenicity of the mosaic Gag (GagM) was compared to a naturally occurring subtype C Gag (GagN) using a DNA homologous vaccination regimen. DNA-GagN expresses a natural Gag with a sequence that was closest to the consensus sequence of subtype C viruses sampled in South Africa. DNA-GagM homologous vaccination induced cumulative HIV-1 Gag-specific IFN-γ ELISPOT responses that were 6.5-fold higher than those induced by the DNA-GagN vaccination. Similarly, DNA-GagM vaccination generated 7-fold higher levels of cytokine-positive CD8+ T cells than DNA-GagN, indicating that this subtype C mosaic Gag elicits far more potent immune responses than a consensus-type Gag. Cells transfected and infected with DNA-GagM and MVA-GagM respectively, expressed high levels of GagM and produced budding virus-like particles. Our data indicates that a heterologous prime boost regimen using DNA and MVA vaccines expressing HIV-1 subtype C mosaic Gag is highly immunogenic in mice and warrants further investigation in non-human primates.
Highlights
Despite the reduction of deaths associated with HIV-1 infection and HIV-1-related illnesses over recent years [1], attributable to expansion of educational programs, use of condoms, male circumcision, as well as the use of anti-retroviral (ARV) drugs, the best long-term means of preventing the spread of this epidemic is a prophylactic HIV-1 vaccine.One of the major difficulties faced in developing a successful HIV-1 vaccine is the enormous diversity of the virus
DNA-GagM homologous vaccination induced cumulative HIV-1 Gag-specific IFN-γ ELISPOT responses that were 6.5-fold higher than those induced by the DNA-GagN vaccination
In this paper we show that this computationally generated HIV-1 subtype C mosaic Gag has the properties of a normal HIV-1 Gag protein, is able to form virus-like particles (VLPs) and is more immunogenic than a natural Gag protein
Summary
Despite the reduction of deaths associated with HIV-1 infection and HIV-1-related illnesses over recent years [1], attributable to expansion of educational programs, use of condoms, male circumcision, as well as the use of anti-retroviral (ARV) drugs, the best long-term means of preventing the spread of this epidemic is a prophylactic HIV-1 vaccine.One of the major difficulties faced in developing a successful HIV-1 vaccine is the enormous diversity of the virus. One approach used to overcome this problem is the use of mosaic immunogens which have been computationally designed to overcome this hurdle by maximizing the inclusion of common T cell epitopes. When compared to consensus immunogens, both full length and conserved region polyvalent mosaic immunogens of HIV-1 group M have shown increased breadth and depth of antigen-specific T-cell responses [2,3,4,5]. Studies have shown that mosaic HIV-1 Gag antigens are processed and presented by peripheral blood mononuclear cells (PBMCs) derived from HIV-1-infected individuals [6]. An HIV-1 subtype C mosaic gag gene was chosen in this study as subtype C is the predominant subtype in sub-Saharan Africa
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