Improving the immunogenicity of HIV-1 envelope trimer vaccines
- Rogier W Sanders1
© Sanders; licensee BioMed Central Ltd. 2011
Published: 3 October 2011
An HIV-1 vaccine that induces protective antibodies remains elusive because a number of factors limit the quantity and quality of the antibodies raised against the HIV-1 envelope glycoprotein complex (Env). We hypothesized that targeting Env vaccines directly to immune cells would improve Env-specific antibody responses. To this end we explored two approaches. First, we fused trimeric Env gp140 at the C-terminus to proteins that can target and activate B cells: CD40 ligand (CD40L), B-cell Activating Factor (BAFF), and A PRoliferation-lnducing Ligand (APRIL). Trimeric Env fused to APRIL, BAFF or CD40L triggered the secretion of IgM, IgG and IgA from human B cells in vitro. In particular Env-APRIL induced higher anti-Env antibody responses in rabbits. Env-APRIL was also more efficient at inducing neutralizing responses against various tier 1 viruses. Second, we embedded immunostimulatory proteins within the Env sequence. We replaced the V1V2 domain of Env with granulocyte-macrophage colony-stimulating factor (GM-CSF). Probing with neutralizing antibodies showed that both the Env and GM-CSF components of the chimeric protein were folded correctly. Furthermore, the embedded GM-CSF domain was functional as a cytokine in vitro. Mouse immunization studies demonstrated that chimeric Env-GM-CSF enhanced Env-specific antibody and T cell responses compared to wild-type Env. Collectively, these results show that targeting and activation of immune cells using engineered cytokine domains within the protein can improve the immunogenicity of Env subunit vaccines.
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.