Abstract
To obtain proof of concept for HIV vaccines, we generated recombinant multimeric particles displaying the HIV-1 Envelope (Env) third hypervariable region (V3) as an N-terminal fusion protein on the E2 subunit of the pyruvate dehydrogenase complex of Geobacillus stearothermophilus. The E2 scaffold self-assembles into a 60-mer core that is 24 nm in diameter, with a molecular weight of 1.5 MDa, similar to a virus like particle with up to 60 copies of a heterologous protein accessible on the surface. Env(V3)-E2 multimers were tested alone and in combination with Env(gp160) DNA in mice and rabbits. Following two or more co-immunizations with Env(V3)-E2 and Env gp160 DNA, all 18 rabbits developed potent autologous neutralizing antibodies specific for V3 in six weeks. These neutralizing antibodies were sustained for 16 weeks without boosting, and comparable responses were obtained when lipopolysaccharide, a contaminant from expression in E. coli, was removed. Co-immunizations of Env(V3)-E2 and DNA expressing gp160 elicited moderate CD8-specific responses and Env-specific antibodies in mice. Co-immunization with DNA and E2 was superior to individual or sequential vaccination with these components in eliciting both neutralizing antibodies in rabbits and CD8+ T cell responses in mice. Co-immunization with DNA and multimeric E2 scaffolds appears to offer a highly effective means of eliciting rapid, specific, and sustained immune responses that may be a useful approach for other vaccine targets.
Highlights
Despite the fact that HIV-1 utilizes highly effective mechanisms of immune evasion [1,2,3], most subjects develop both neutralizing antibodies (NAbs) and CD8+ T cell responses, albeit too late to clear the established infection
We evaluated the immunogenicity of Env(V3)-E2 60-mer particles in mice and in rabbits to determine whether presentation of HIV-1 V3 on E2 could focus the immune responses to the neutralization and CTL epitopes
Cell epitopes and to elicit CTL and antibody responses directed to HIV-1 Gag-p17 in HLA-A1 transgenic mice [36]
Summary
Despite the fact that HIV-1 utilizes highly effective mechanisms of immune evasion [1,2,3], most subjects develop both neutralizing antibodies (NAbs) and CD8+ T cell responses, albeit too late to clear the established infection. A major challenge in vaccine design has been to identify antigen presentation and delivery systems capable of eliciting strong, sustained immunity that can either prevent HIV-1 infection or provide a very high degree of control of viremia post-challenge. Vaccine approaches for HIV-1 have included recombinant viral vectors, DNA, and protein subunits, tested alone and in prime-boost combinations. These vaccines focused on eliciting cellular responses [13,14,15,16,17,18,19] following the failure of the VaxGen gp120 trial [20,21], but T cell responses induced by adenovirus in the STEP trial were insufficient for protection [22]. Cholera toxin B displaying the HIV-1 Env third hypervariable region (V3) elicited moderate cross-NAbs in rabbits [30] which may be due to its conserved structural features [31]
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