HIV-1 envelope trimer fusion proteins and their applications

HIV-1 is a major threat to global health and a vaccine is not yet on the horizon. A successful HIV-1 vaccine should probably induce HIV-1 neutralizing antibodies that target the envelope glycoprotein (Env) trimer on the outside of the virion. A possible starting point for such a vaccine are soluble versions of the native Env trimer.
In this thesis research we have fused different heterologous molecules to soluble Env proteins to increase their immunogenicity and to generate tools to address a variety of research questions. We found that attachment of a cytokine to an Env trimer induced increased antibody responses against Env and that heterologous trimerization domains that are commonly used for making Env trimers are highly immunogenic.
A stable soluble mimic of the native viral Env trimer became available during this thesis work. We used these soluble native-like Env trimers to study broadly neutralizing HIV-1 antibodies. These trimers also facilitated the generation of fusion constructs consisting of an Env trimer with green fluorescent protein attached or an Env trimer containing a long polymeric tail to shield unwanted epitopes. We also fused native-like Env trimers to ferritin nanoparticles, which improved the immunogenicity of these trimers. In summary, we showed that Env trimers are suitable for generating fusion constructs for different applications, including for generating vaccine candidates with improved immunogenicity.