HIV-1 envelope glycoproteins with costimulatory domains for vaccine applications

Abstract

Various immuno-evasive properties of the HIV-1 Env subunit limit the value of traditional vaccine strategies and urge us to explore different vaccine approaches. We have been working on a vaccine strategy in which we designed dual-functional fusion molecules of trimeric HIV-1 Env with a costimulatory molecule. First, we generated Env-GM-CSF trimers by replacing the V1V2 domain of Env with GM-CSF (chapter 2). This construct was further optimized in the study described in chapter 3. Another fusion molecule, Env-IL-21, was generated using a similar design strategy by replacement of the V1V2 domain with IL-21 and its activity was assessed in vitro (chapter 4). Next we studied both Env-GM-CSF and Env-IL-21 trimers in vivo by immunizing rabbits and mice (chapter 5). We found that both molecules induced a potent immune response against the cytokine inserts, irrespective of their location in the fusion protein. In chapter 6 we describe in vitro and in vivo studies on the bioactivity of Env trimers fused to APRIL. Furthermore, we describe a strategy to immunosilence this trimerization domain by covering its protein surface with glycans. Finally, in the last research chapter (chapter 8), we report on the in vitro and in vivo activity of APRIL fused to a next generation native-like Env trimer mimetic, BG505 SOSIP.664 gp140. We note that all our immunization were done with plasmids encoding Env-costimulatory fusion molecules. Different immunization approach may lead to different effects