A chimeric HIV-1 envelope glycoprotein trimer with an embedded granulocyte-macrophage colony-stimulating factor (GM-CSF) domain induces enhanced antibody and T cell responses.

Abstract

An effective HIV-1 vaccine should ideally induce strong humoral and cellular immune responses that provide sterilizing immunity over a prolonged period. Current HIV-1 vaccines have failed in inducing such immunity. The viral envelope glycoprotein complex (Env) can be targeted by neutralizing antibodies to block infection, but several Env properties limit the ability to induce an antibody response of sufficient quantity and quality. We hypothesized that Env immunogenicity could be improved by embedding an immunostimulatory protein domain within its sequence. A stabilized Env trimer was therefore engineered with the granulocyte-macrophage colony-stimulating factor (GM-CSF) inserted into the V1V2 domain of gp120. 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 with 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.

DOI: 10.1074/jbc.M111.229625

Cite this paper

@article{Montfort2011ACH, title={A chimeric HIV-1 envelope glycoprotein trimer with an embedded granulocyte-macrophage colony-stimulating factor (GM-CSF) domain induces enhanced antibody and T cell responses.}, author={Thijs van Montfort and Mark Melchers and G. Isik and Sergey Menis and Po-Ssu Huang and Katie Matthews and Elizabeth Michael and Ben Berkhout and William R. Schief and John P. Moore and Rogier W. Sanders}, journal={The Journal of biological chemistry}, year={2011}, volume={286 25}, pages={22250-61} }